Pharmaceutical Formulation Containing Gelling Agent

ABSTRACT

Disclosed in certain embodiments is a controlled release oral dosage form comprising a therapeutically effective amount of a drug susceptible to abuse together with one or more pharmaceutically acceptable excipients; the dosage form further including a gelling agent in an effective amount to impart a viscosity unsuitable for administration selected from the group consisting of parenteral and nasal administration to a solubilized mixture formed when the dosage form is crushed and mixed with from about 0.5 to about 10 ml of an aqueous liquid; the dosage form providing a therapeutic effect for at least about 12 hours when orally administered to a human patient.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.13/726,324, filed on Dec. 24, 2012, which is a continuation of U.S.patent application Ser. No. 13/349,449, filed Jan. 12, 2012, which is acontinuation of U.S. patent application Ser. No. 12/653,115, filed Dec.8, 2009, which is a continuation of U.S. patent application Ser. No.10/214,412, filed Aug. 6, 2002, which claims the benefit of U.S.Provisional Application No. 60/310,534, filed Aug. 6, 2001. The contentsof these applications are hereby incorporated by reference in theirentirety.

BACKGROUND OF THE INVENTION

Opioid analgesics are sometimes the subject of abuse. Typically, aparticular dose of an opioid analgesic is more potent when administeredparenterally as compared to the same dose administered orally.Therefore, one popular mode of abuse of oral opioid formulationsinvolves the extraction of the opioid from the dosage form, and thesubsequent injection of the opioid (using any “suitable” vehicle forinjection) in order to achieve a “high.” Also, some formulations can betampered with in order to provide the opioid agonist contained thereinbetter available for illicit use. For example, a controlled releaseopioid agonist formulation can be crushed in order to provide the opioidcontained therein available for immediate release upon oral or nasaladministration. An opioid formulation can also be abusable byadministration of more than the prescribed dose of the drug.

Opioid antagonists have been combined with certain opioid agonists inorder to deter the parenteral abuse of opioid agonists. In the priorart, the combination of immediate release pentazocine and naloxone hasbeen utilized in tablets available in the United States, commerciallyavailable as Talwin® Nx from Sanofi-Winthrop. Talwin® Nx containsimmediate release pentazocine hydrochloride equivalent to 50 mg base andnaloxone hydrochloride equivalent to 0.5 mg base. A fixed combinationtherapy comprising tilidine (50 mg) and naloxone (4 mg) has beenavailable in Germany for the management of pain since 1978 (Valoron® N,Goedecke). A fixed combination of buprenorphine and naloxone wasintroduced in 1991 in New Zealand (Temgesic® Nx, Reckitt & Colman) forthe treatment of pain.

Purdue Pharma EP currently markets sustained-release oxycodone in dosageforms containing 10, 20, 40, and 80 mg oxycodone hydrochloride under thetradename OxyContin.

U.S. Pat. Nos. 5,266,331; 5,508,042; 5,549,912 and 5,656,295 disclosesustained release oxycodone formulations.

U.S. Pat. Nos. 4,769,372 and 4,785,000 to Kreek describe methods oftreating patients suffering from chronic pain or chronic cough withoutprovoking intestinal dysmotility by administering 1 to 2 dosage unitscomprising from about 1.5 to about 100 mg of opioid analgesic orantitussive and from about 1 to about 18 mg of an opioid antagonisthaving little to no systemic antagonist activity when administeredorally, from 1 to 5 times daily.

U.S. Pat. No. 6,228,863 to Palermo et al. describes compositions andmethods of preventing abuse of opioid dosage forms.

WO 99/32119 to Kaiko et al. describes compositions and methods ofpreventing abuse of opioid dosage forms.

U.S. Pat. No. 5,472,943 to Crain et al. describes methods of enhancingthe analgesic potency of bimodally acting opioid agonists byadministering the agonist with an opioid antagonist.

U.S. Pat. No. 3,980,766 to Shaw et al., is related to drugs which aresuitable for therapy in the treatment of narcotic drug addiction by oraluse, e.g., methadone, formulated to prevent injection abuse throughconcentration of the active component in aqueous solution byincorporating in a solid dosage or tablet form of such drug aningestible solid having thickening properties which cause rapid increasein viscosity upon concentration of an aqueous solution thereof.

However, there still exists a need for a safe and effective treatment ofpain with opioid analgesic dosage forms which are less subject to abusethan current therapies.

All documents cited herein, including the foregoing, art incorporated byreference in their entireties for all purposes.

OBJECTS AND SUMMARY OF THE INVENTION

It is an object of certain embodiments of the invention to provide anoral dosage form of an opioid analgesic which is subject to lessparenteral abuse than other dosage forms.

It is an object of certain embodiments of the invention to provide anoral dosage form of an opioid analgesic which is subject to lessintranasal abuse than other dosage forms.

It is an object of certain embodiments of the invention to provide anoral dosage form of an opioid analgesic which is subject to less oralabuse than other dosage forms.

It is a further object of certain embodiments of the invention toprovide an oral dosage form of an opioid analgesic which is subject toless diversion than other dosage forms.

It is a further object of certain embodiments of the invention toprovide a method of treating pain in human patients with an oral dosageform of an opioid analgesic while reducing the abuse potential of thedosage form.

It is a further object of certain embodiments of the invention toprovide a method of manufacturing an oral dosage form of an opioidanalgesic such that it has less abuse potential.

These objects and others are achieved by the present invention, which isdirected in part to an oral dosage form comprising an opioid analgesic;and at least one aversive agent for reducing the abuse of the opioidanalgesic.

In certain embodiments of the present invention, the oral dosage formsof the present invention comprising an opioid analgesic; and an aversiveagent or agents as a component(s) of the dosage form helps to preventinjection, inhalation, and/or oral abuse by decreasing the“attractiveness” of the dosage form to a potential abuser.

In certain embodiments of the present invention, the dosage formcomprises an aversive agent such as a bittering agent to discourage anabuser from tampering with the dosage form and thereafter inhaling orswallowing the tampered dosage form. Preferably, the bittering agent isreleased when the dosage form is tampered with and provides anunpleasant taste to the abuser upon inhalation and/or swallowing of thetampered dosage form.

In certain embodiments of the present invention, the dosage formcomprises an aversive agent such as an irritant to discourage an abuserfrom tampering with the dosage form and thereafter inhaling, injecting,or swallowing the tampered dosage form. Preferably, the irritant isreleased when the dosage form is tampered with and provides a burning orirritating effect to the abuser upon inhalation, injection, and/orswallowing of the tampered dosage form.

In certain embodiments of the present invention, the dosage formcomprises an aversive agent such as a gelling agent to discourage anabuser from tampering with the dosage form and thereafter inhaling,injecting, and/or swallowing the tampered dosage form. Preferably, thegelling agent is released when the dosage form is tampered with andprovides a gel-like quality to the tampered dosage form which slows theabsorption of the opioid analgesic such that an abuser is less likely toobtain a rapid “high”. In certain preferred embodiments, when the dosageform is tampered with and exposed to a small amount (e.g., less thanabout 10 ml) of an aqueous liquid (e.g., water), the dosage form will beunsuitable for injection and/or inhalation. Upon the addition of theaqueous liquid, the tampered dosage form preferably becomes thick andviscous, rendering it unsuitable for injection. The term “unsuitable forinjection” is defined for purposes of the present invention to mean thatone would have substantial difficulty injecting the dosage form (e.g.,due to pain upon administration or difficulty pushing the dosage formthrough a syringe) due to the viscosity imparted on the dosage form,thereby reducing the potential for abuse of the opioid analgesic in thedosage form. In certain embodiments, the gelling agent is present insuch an amount in the dosage form that attempts at evaporation (by theapplication of heat) to an aqueous mixture of the dosage form in aneffort to produce a higher concentration of the therapeutic agent,produces a highly viscous substance unsuitable for injection.

When nasally inhaling the tampered dosage form, the gelling agent canbecome gel like upon administration to the nasal passages due to themoisture of the mucous membranes. This also makes such formulationsaversive to nasal administration, as the gel will stick to the nasalpassage and minimize absorption of the abusable substance. In certainembodiments of the present invention, the dosage form comprises acombination of any or all of the aforementioned aversive agents (e.g., abittering agent, an irritant, and/or a gelling agent) to discourage anabuser from tampering with the dosage form and thereafter inhaling,injecting, and/or swallowing the tampered dosage form.

Embodiments specifically contemplated include bittering agent; gellingagent; irritant; bittering agent and gelling agent; bittering agent andirritant; gelling agent and irritant; and bittering agent and gellingagent and irritant.

In certain preferred embodiments, the dosage forms are controlledrelease oral dosage forms comprising a therapeutically effective amountof an opioid analgesic with one or more of the aversive agents describedabove such that the dosage form provides effective pain relief for atleast about 12 hours, or at least about 24 hours when orallyadministered to a human patient.

In certain embodiments of the present invention the aversive agentpresent in the dosage form is present in a substantially non-releasableform (i.e., “sequestered”) when the dosage form is administered intactas directed. Preferably, because the aversive agent is present in thedosage form in a substantially non-releasable form, it is notsubstantially released in the gastrointestinal tract when the dosageform is orally administered intact.

In other embodiments, the aversive agent may not be “sequestered” asdisclosed above wherein the aversive agent is not released or minimallyreleased from an intact dosage form, but may have a modified orsustained release so as not to dump the aversive agent in a particularsection of the gastrointestinal tract, e.g. the stomach, where it maycause an unwanted effect such as excessive irritation. The aversiveagent can be combined with an enteric carrier to delay its release orcombined with a carrier to provide a sustained release of the aversiveagent. However, it is contemplated in the present invention that theaversive agent will preferably not have any significant side effect(e.g., gastrointestinal side effect) even if all of the aversive agentis immediately released upon oral administration of an intact dosageform as directed.

The aversive agent(s) can also be in the dosage form in releasable formand non-releasable form in any combination. For example, a dosage formcan have a bittering agent, irritant, gel or combination thereof inreleasable form and non-releasable form as disclosed in U.S. applicationentitled “Pharmaceutical Formulations Containing Opioid Agonist,Releasable Antagonist, and Sequestered Antagonist” filed Aug. 6, 2002,the disclosure of which is hereby incorporated by reference in itsentirety.

The term “aversive agent” is defined for purposes of the presentinvention to mean a bittering agent, an irritant, a gelling agent, orcombinations thereof.

The term “tampered dosage form” is defined for purposes of the presentinvention to mean that the dosage form has been manipulated bymechanical, thermal, and/or chemical means which changes the physicalproperties of the dosage form, e.g., to liberate the opioid agonist forimmediate release if it is in sustained release form, or to make theopioid agonist available for inappropriate use such as administration byan alternate route, e.g., parenterally. The tampering can be, e.g., bymeans of crushing, shearing, grinding, chewing, dissolution in asolvent, heating, (e.g., greater than about 45° C.), or any combinationthereof.

The term “substantially non-releasable form” for purposes of the presentinvention refers to an aversive agent that is not released orsubstantially not released at one hour after the intact dosage formcontaining an opioid agonist and at least one aversive agent is orallyadministered (i.e., without having been tampered with). The aversiveagent in a substantially non-releasable form may be prepared inaccordance with the teachings of U.S. application Ser. No. 09/781,081,entitled “Tamper Resistant Oral Opioid Agonist Formulations” filed Feb.8, 2001, the disclosure of which is hereby incorporated by reference inits entirety, which describes a dosage form comprising an opioidantagonist in a substantially non-releasable form. For purposes of thepresent invention, the amount released after oral administration of theintact dosage form may be measured in-vitro via the dissolution at 1hour of the dosage form in 900 ml of Simulated Gastric Fluid using a USPType II (paddle) apparatus at 75 rpm at 37.degree. C. Such a dosage formis also referred to as comprising a “sequestered aversive agent”depending on the agent or agents which are not released or substantiallynot released. In certain preferred embodiments of the invention, thesubstantially non-releasable form of the aversive agent is resistant tolaxatives (e.g., mineral oil) used to manage delayed colonic transit andresistant to achlorhydric states. Preferably, the aversive agent is notreleased or not substantially released 4, 8, 12 and/or 24 hours afteroral administration.

The phrase “analgesic effectiveness” is defined for purposes of thepresent invention as a satisfactory reduction in or elimination of pain,along with a tolerable level of side effects, as determined by the humanpatient.

The term “sustained release” is defined for purposes of the presentinvention as the release of the opioid analgesic from the oral dosageform at such a rate that blood (e.g., plasma) concentrations (levels)are maintained within the therapeutic range but below toxic levels overan extended period of time, e.g., from about 12 to about 24 hours ascompared to an immediate release product. Preferably the sustainedrelease is sufficient to provide a twice-a-day or a once-a-dayformulation.

The term “particles” of aversive agent, as used herein, refers togranules, spheroids, beads or pellets comprising the aversive agent. Incertain preferred embodiments, the aversive agent particles are about0.2 to about 2 mm in diameter, more preferably about 0.5 to about 2 mmin diameter.

The term “parenterally” as used herein includes subcutaneous injections,intravenous injections, intramuscular injections, intrasternalinjections, infusion techniques, or other methods of injection known inthe art.

The term “inhaled” as used herein includes trans-mucosal,trans-bronchial, and trans-nasal abuse.

The term “bittering agent” as used herein includes a compound used toimpart a bitter taste, bitter flavor, etc., to an abuser administering atampered dosage form of the present invention.

The term “irritant” as used herein includes a compound used to impart anirritating or burning sensation to an abuser administering a tampereddosage form of the present invention.

The term “gelling agent” as used herein includes a compound orcomposition used to impart gel-like or thickening quality to a tampereddosage form upon the addition of moisture or liquid.

DETAILED DESCRIPTION OF THE INVENTION

The aversive agents of the present invention are preferably for use inconnection with oral dosage forms including opioid analgesics, whichprovide valuable analgesia but which may be abused. This is particularlytrue for controlled release opioid analgesic products which have a largedose of opioid analgesic intended to be released over a period of timein each dosage unit. Drug abusers typically may take acontrolled-release product and crush, shear, grind, chew, dissolveand/or heat, extract or otherwise damage the product so that the fullcontents of the dosage form become available for immediate absorption byinjection, inhalation, and/or oral consumption.

In certain embodiments, the present invention comprises a method forpreventing or deterring the abuse of opioid analgesics by the inclusionof at least one aversive agent in the dosage form with the opioidanalgesic.

In certain alternative embodiments, the present invention comprises amethod for preventing or deterring the abuse of drugs other than opioidanalgesics which may also be the subject of abuse, by including at leastone of the aversive agents described herein in a dosage form comprisingthe drug other than an opioid analgesic which is the subject of abuse.

In certain embodiments of the present invention wherein the dosage formincludes an aversive agent comprising a bittering agent, variousbittering agents can be employed including, for example and withoutlimitation, natural, artificial and synthetic flavor oils and flavoringaromatics and/or oils, oleoresins and extracts derived from plants,leaves, flowers, fruits, and so forth, and combinations thereof.Nonlimiting representative flavor oils include spearmint oil, peppermintoil, eucalyptus oil, oil of nutmeg, allspice, mace, oil of bitteralmonds, menthol and the like. Useful bittering agents can beartificial, natural and synthetic fruit flavors such as citrus oilsincluding lemon, orange, lime, grapefruit, and fruit essences and soforth. Additional bittering agents include sucrose derivatives (e.g.,sucrose octaacetate), chlorosucrose derivatives, quinine sulphate, andthe like. The preferred bittering agent for use in the present inventionis Denatonium Benzoate NF-Anhydrous, sold under the name Bitrex™(Macfarlan Smith Limited, Edinburgh, UK).

With the inclusion of a bittering agent in the formulation, the intakeof the tampered dosage form produces a bitter taste upon inhalation ororal administration which in certain embodiments spoils or hinders thepleasure of obtaining a high from the tampered dosage form, andpreferably prevents the abuse of the dosage form.

A bittering agent may be added to the formulation in an amount of lessthan about 50% by weight preferably less than about 10% by weight, mostpreferably less than about 5% by weight of the dosage form, and mostpreferably in an amount ranging from about 0.1 to 1.0 percent by weightof the dosage form, depending on the particular bittering agent(s) used.A dosage form including a bittering agent preferably discouragesimproper usage of the tampered dosage form by imparting a disagreeabletaste or flavor to the tampered dosage form.

In certain embodiments of the present invention wherein the dosage formincludes an aversive agent comprising an irritant, various irritants canbe employed including, for example and without limitation capsaicin, acapsaicin analog with similar type properties as capsaicin, and thelike. Some capsaicin analogues or derivatives include for example andwithout limitation, resiniferatoxin, tinyatoxin, heptanoylisobutylamide,heptanoyl guaiacylamide, other isobutylamides or guaiacylamides,dihydrocapsaicin, homovanillyl octylester, nonanoyl vanillylamide, orother compounds of the class known as vanilloids. Resiniferatoxin isdescribed, for example, in U.S. Pat. No. 5,290,816 (Blumberg), issuedMar. 1, 1994. U.S. Pat. No. 4,812,446 (Brand), issued Mar. 14, 1989,describes capsaicin analogs and methods for their preparation. Further,U.S. Pat. No. 4,424,205 (LaHann et al.), issued Jan. 3, 1984, citeNewman, “Natural and Synthetic Pepper-Flavored Substances” published in1954 as listing pungency of capsaicin-like analogs. Ton et al., BritishJournal of Pharmacology, 10, pp. 175-182 (1955) discuss pharmacologicalactions of capsaicin and its analogs.

With the inclusion of an irritant (e.g., capsaicin) in the dosage form,when the dosage form is tampered with, the capsaicin imparts a burningor discomforting quality to the abuser to preferably discourage theinhalation, injection, or oral administration of the tampered dosageform, and preferably to prevent the abuse of the dosage form. Suitablecapsaicin compositions include capsaicin (trans8-methyl-N-vanillyl-6-noneamide or analogues thereof in a concentrationbetween about 0.00125% and 50% by weight, preferably between about 1 andabout 7.5% by weight, and most preferably, between about 1 and about 5%by weight of the dosage form.

In certain embodiments of the present invention wherein the dosage formincludes an aversive agent comprising a gelling agent, various gellingagents can be employed including, for example and without limitation,sugars or sugar derived alcohols, such as mannitol, sorbitol, and thelike, starch and starch derivatives, cellulose derivatives, such asmicrocrystalline cellulose, sodium cahoxymethyl cellulose,methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose, and hydroxypropyl methylcellulose, attapulgites, bentonites,dextrins, alginates, carrageenan, gum tragacanth, gum acacia, guar gum,xanthan gum, pectin, gelatin, kaolin, lecithin, magnesium aluminumsilicate, the carbomers and carbopols, polyvinylpyrrolidone,polyethylene glycol, polyethylene oxide, polyvinyl alcohol, silicondioxide, surfactants, mixed surfactant/wetting agent systems,emulsifiers, other polymeric materials, and mixtures thereof, etc. Incertain preferred embodiments, the gelling agent is xanthan gum. Inother preferred embodiments, the gelling agent of the present inventionis pectin. The pectin or pectic substances useful for this inventioninclude not only purified or isolated pectates but also crude naturalpectin sources, such as apple, citrus or sugar beet residues which havebeen subjected, when necessary, to esterification or de-esterification,e.g., by alkali or enzymes. Preferably, the pectins used in thisinvention are derived from citrus fruits such as lime, lemon,grapefruit, and orange.

With the inclusion of a gelling agent in the dosage form, when thedosage form is tampered with, the gelling agent preferably imparts agel-like quality to the tampered dosage form which preferably spoils orhinders the pleasure of obtaining a rapid high from the tampered dosageform due to the gel like consistency in contact with the mucousmembrane, and in certain embodiments, prevents the abuse of the dosageform by minimizing absorption, e.g. in the nasal passages. A gellingagent may be added to the formulation in a ratio of gelling agent toopioid agonist of from about 1:40 to about 40:1 by weight, preferablyfrom about 1:1 to about 30:1 by weight, and more preferably from about2:1 to about 10:1 by weight of the opioid agonist. In certainalternative embodiments, the gelling agent may be present in a ratio tothe opioid agonist of from about 1:15 to about 15:1, preferably in aratio of from about 1:8 to about 8:1, and more preferably from about 1:3to about 3:1 by weight of the opioid agonist.

In certain other embodiments, the dosage form forms a viscous gel afterthe dosage form is tampered with, dissolved in an aqueous liquid (fromabout 0.5 to about 10 ml and preferably from 1 to about 5 ml), causingthe resulting mixture to have a viscosity of at least about 10 cP. Mostpreferably, the resulting mixture will have a viscosity of at leastabout 60 cP.

In certain other embodiments, the dosage form forms a viscous gel afterthe dosage form is tampered with, dissolved in an aqueous liquid (fromabout 0.5 to about 10 ml and preferably from 1 to about 5 ml) and thenheated (e.g., greater than about 45° C.), causing the resulting mixtureto have a viscosity of at least about 10 cP. Most preferably, theresulting mixture will have a viscosity of at least about 60 cP.

In certain embodiments, the dosage form may include one or more of theaforementioned aversive agents. For safety reasons, the amount of thebittering agent, irritant, or gelling agent in a formulation of thepresent invention should not be toxic to humans.

In certain embodiments, the aversive agent included in the dosage formmay be in a substantially non-releasable form. Where the aversive agentis in a substantially non-releasable form, the substantiallynon-releasable form of the aversive agent comprises an aversive agentthat is formulated with one or more pharmaceutically acceptablehydrophobic materials, such that the aversive agent is not released orsubstantially not released during its transit through thegastrointestinal tract when administered orally as intended, withouthaving been tampered with.

In certain embodiments of the present invention, the substantiallynon-releasable form of the aversive agent is vulnerable to mechanical,thermal and/or chemical tampering, e.g., tampering by means of crushing,shearing, grinding, chewing and/or dissolution in a solvent incombination with heating (e.g., greater, than about 45° C.) of the oraldosage form. When the dosage form is tampered with, the integrity of thesubstantially non-releasable form of the aversive agent will becompromised, and the aversive agent will be made available to bereleased. In certain embodiments, when the dosage form is chewed,crushed or dissolved and heated in a solvent, the release of theaversive agent hinders, deters or prevents the administration of thetampered dosage form orally, intranasally, parenterally and/orsublingually.

The opioid agonists useful in the present invention include, but are notlimited to, alfentanil, allylprodine, alphaprodine, anileridine,benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene,codeine, desomorphine, dextromoramide, dezocine, diampromide,diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol,dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone,eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine,etonitazene, etorphine, dihydroetorphine, fentanyl and derivatives,heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone,ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine,meptazinol, metazocine, methadone, metopon, morphine, myrophine,narceine, nicomorphine, norlevorphanol, normethadone, nalorphine,nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone,papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine,phenoperidine, piminodine, piritramide, propheptazine, promedol,properidine, propoxyphene, sufentanil, tilidine, tramadol, mixtures ofany of the foregoing, salts of any of the foregoing, and the like. Incertain embodiments, the amount of the opioid agonist in the claimedopioid composition may be about 75 ng to about 750 mg.

In certain preferred embodiments, the opioid agonist is selected fromthe group consisting of hydrocodone, morphine, hydromorphone, oxycodone,codeine, levorphanol, meperidine, methadone, oxymorphone, buprenorphine,fentanyl and derivatives thereof, dipipanone, heroin, tramadol,etorphine, dihydroetorphine, butorphanol, levorphanol, or salts thereofor mixtures thereof. In certain preferred embodiments, the opioidagonist is oxycodone or hydrocodone.

In embodiments in which the opioid analgesic comprises hydrocodone,dosage forms may include analgesic doses from about 2 mg to about 50 mgof hydrocodone bitartrate. In embodiments in which the opioid analgesiccomprises hydromorphone the dosage form may include from about 2 mg toabout 64 mg hydromorphone hydrochloride. In embodiments in which theopioid analgesic comprises morphine, the dosage form may include fromabout 2.5 mg to about 800 mg morphine sulfate, by weight. In embodimentsin which the opioid analgesic comprises oxycodone, the dosage form mayinclude from about 2.5 mg to about 320 mg oxycodone hydrochloride. Thedosage form may contain more than one opioid analgesic to provide atherapeutic effect. Alternatively, the dosage form may contain molarequivalent amounts of other salts of the opioids useful in the presentinvention.

Hydrocodone is a semisynthetic narcotic analgesic and antitussive withmultiple central nervous system and gastrointestinal actions.Chemically, hydrocodone is 4,5-epoxy-3-methoxy-17-methylmorphinan-6-one,and is also known as dihydrocodeinone. Like other opioids, hydrocodonemay be habit forming and may produce drug dependence of the morphinetype. In excess doses hydrocodone, like other opium derivatives, willdepress respiration.

Oral hydrocodone is also available in Europe (Belgium, Germany, Greece,Italy, Luxembourg, Norway and Switzerland) as an antitussive agent. Aparenteral formulation is also available in Germany as an antitussiveagent. For use as an analgesic, hydrocodone bitartrate is commerciallyavailable in the United States only as a fixed combination withnon-opiate drugs (i.e., ibuprofen, acetaminophen, aspirin, etc.) forrelief of moderate or moderately severe pain.

A common dosage form of hydrocodone is in combination withacetaminophen, and is commercially available, e.g., as Lortab® in theU.S. from UCB Pharma. Inc. as 2.5/500 mg, 5/500 mg, 7.5/500 mg and10/500 mg hydrocodone/acetaminophen tablets. Tablets are also availablein the ratio of 7.5 mg hydrocodone bitartrate and 650 mg acetaminophen;and 7.5 mg hydrocodone bitartrate and 750 mg acetaminophen. Hydrocodonein combination with aspirin is given in an oral dosage form to adultsgenerally in 1-2 tablets every 4-6 hours as needed to alleviate pain.The tablet form is 5 mg hydrocodone bitartrate and 224 mg aspirin with32 mg caffeine; or 5 mg hydrocodone bitartrate and 500 mg aspirin. Arelatively new formulation comprises hydrocodone bitartrate andibuprofen. Vicoprofen®, commercially available in the U.S. from KnollLaboratories, is a tablet containing 7.5 mg hydrocodone bitartrate and200 mg ibuprofen. The present invention is contemplated to encompass allsuch formulations, with the inclusion of one or more aversive agents asdescribed herein.

Oxycodone, chemically known as4,5-expoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one, is an opioidagonist whose principal therapeutic action is analgesia. Othertherapeutic effects of oxycodone include anxiolysis, euphoria andfeelings of relaxation. The precise mechanism of its analgesic action isnot known, but specific CNS opioid receptors for endogenous compoundswith opioid-like activity have been identified throughout the brain andspinal cord and play a role in the analgesic effects of this drug.

Oxycodone is commercially available in the United States, e.g., asOxycontin.® from Purdue Pharma L.P. as controlled-release tablets fororal administration containing 10 mg, 20 mg, 40 mg or 80 mg oxycodonehydrochloride, and as OxyIR®, also from Purdue Pharma L.P., asimmediate-release capsules containing 5 mg oxycodone hydrochloride. Thepresent invention is contemplated to encompass all such formulations,with the inclusion of one or more aversive agents as described herein.

Additionally, agents other than opioid analgesics which are subject toabuse may be used in accordance with the present invention in place ofthe opioid analgesics in the dosage form. Certain agents include, forexample and without limitation, tranquilizers, CNS depressants, CNSstimulants, sedative hypnotics and the like. More specifically,barbiturates such as phenobarbital, secobarbital, pentobarbital,butabarbital, talbutal, aprobarbital, mephobarbital, butalbital,pharmaceutically acceptable salts thereof, and the like; benzodiazepinessuch as diazepam, chlordiazepoxide, alprazolam, triazolam, estazolam,clonazepam, flunitrazepam, pharmaceutically acceptable salts thereof,and the like; stimulants such as gamma-hydroxybutyrate,dextroamphetamine, methylphenidate, sibutramine,methylenedioxymethamphetamine, pharmaceutically acceptable saltsthereof, and the like; and other agents such as marinol, meprobamate,carisoprodol, pharmaceutically acceptable salts thereof and the like.

Preparation of Aversive Agent in a Substantially Non-Releasable Form

In certain embodiments of the present invention, an aversive agent in asubstantially non-releasable form may be prepared by combining theaversive agent with one or more of a pharmaceutically acceptablehydrophobic material. For example, aversive agent particles may becoated with coating that substantially prevents the release of theaversive agent, the coating comprising the hydrophobic materials(s).Another example would be an aversive agent that is dispersed in a matrixthat renders the aversive agent substantially non-releasable, the matrixcomprising the hydrophobic materials(s). In certain embodiments, thepharmaceutically acceptable hydrophobic material comprises a cellulosepolymer selected from the group consisting of ethylcellulose, celluloseacetate, cellulose propionate (lower, medium or higher molecularweight), cellulose acetate propionate, cellulose acetate butyrate,cellulose acetate phthalate and cellulose triacetate. An example ofethylcellulose is one that has an ethoxy content of 44 to 55%.Ethylcellulose may be used in the form of an alcoholic solution. Incertain other embodiments, the hydrophobic material comprises polylacticacid, polyglycolic acid or a copolymer of the polylactic andpolyglycolic acid.

In certain embodiments, the hydrophobic material may comprise acellulose polymer selected from the group consisting of cellulose ether,cellulose ester, cellulose ester ether, and cellulose. The cellulosicpolymers have a degree of substitution, D.S., on the anhydroglucoseunit, from greater than zero and up to 3 inclusive. By degree ofsubstitution is meant the average number of hydroxyl groups present onthe anhydroglucose unit comprising the cellulose polymer that arereplaced by a substituting group. Representative materials include apolymer selected from the group consisting of cellulose acylate,cellulose diacylate, cellulose triacylate, cellulose acetate, cellulosediacetate, cellulose triacetate, mono, di, and tricellulose alkanylates,mono, di, and tricellulose aroylates, and mono, di, and tricellulosealkenylates. Exemplary polymers include cellulose acetate having a D.S.and an acetyl content up to 21%; cellulose acetate having an acetylcontent up to 32 to 39.8%; cellulose acetate having a D.S. of 1 to 2 andan acetyl content of 21 to 35%; cellulose acetate having a D.S. of 2 to3 and an acetyl content of 35 to 44.8%.

More specific cellulosic polymers include cellulose propionate having aD.S. of 1.8 and a propyl content of 39.2 to 45 and a hydroxyl content of2.8 to 5.4%; cellulose acetate butyrate having a D.S. of 1.8, an acetylcontent of 13 to 15% and a butyryl content of 34 to 39%; celluloseacetate butyrate having an acetyl content of 2 to 29%, a butyryl contentof 17 to 53% and a hydroxyl content of 0.5 to 4.7%; cellulose triacylatehaving a D.S. of 2.9 to 3 such as cellulose triacetate, cellulosetrivalerate, cellulose trilaurate, cellulose tripalmitate, cellulosetrisuccinate, and cellulose trioctanoate; cellulose diacylates having aD.S. of 2.2 to 2.6 such as cellulose disuccinate, cellulose dipalmitate,cellulose dioctanoate, cellulose dipentanoate, and coesters of cellulosesuch as cellulose acetate butyrate, cellulose acetate octanoate butyrateand cellulose acetate propionate.

Additional cellulose polymers useful for preparing an aversive agent ina substantially non-releasable form include acetaldehyde dimethylcellulose acetate, cellulose acetate ethylcarbamate, cellulose acetatemethylcarbamate, and cellulose acetate dimethylaminocellulose acetate.

Acrylic polymers useful for preparation of the aversive agent in asubstantially non-releasable form include, but are not limited to,acrylic resins comprising copolymers synthesized from acrylic andmethacrylic acid esters (e.g., the copolymer of acrylic acid lower alkylester and methacrylic acid lower alkyl ester) containing about 0.02 to0.03 mole of a tri (lower alkyl) ammonium group per mole of the acrylicand methacrylic monomers used. An example of a suitable acrylic resin isa polymer manufactured by Rohm Pharma GmbH and sold under the Eudragit®RS trademark. Eudragit RS30D is preferred. Eudragit® RS is a waterinsoluble copolymer of ethyl acrylate (EA), methyl methacrylate (MM) andtrimethylammoniumethyl methacrylate chloride (TAM) in which the molarratio of TAM to the remaining components (EA and MM) is 1:40. Acrylicresins such as Eudragit® RS may be used in the form of an aqueoussuspension.

In certain embodiments of the invention, the acrylic polymer may beselected from the group consisting of acrylic acid and methacrylic acidcopolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates,cyanoethyl methacrylate, poly(acrylic acid), poly(methacrylic acid),methacrylic acid alkylamide copolymer, poly(methyl methacrylate),polymethacrylate, poly(methyl methacrylate) copolymer, polyacrylamide,aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), andglycidyl methacrylate copolymers.

When the aversive agent in a substantially non-releasable form comprisesaversive agent particles coated with a coating that renders the aversiveagent substantially non-releasable, and when a cellulose polymer or anacrylic polymer is used for preparation of the coating composition,suitable plasticizers, e.g., acetyl triethyl citrate and/or acetyltributyl citrate may also be admixed with the polymer. The coating mayalso contain additives such as coloring agents, talc and/or magnesiumstearate, which are well known in the coating art.

The coating composition may be applied onto the aversive agent particlesby spraying it onto the particles using any suitable spray equipmentknown in the art. For example, a Wuster fluidized-bed system may be usedin which an air jet, injected from underneath, fluidizes the coatedmaterial and effects drying while the insoluble polymer coating issprayed on. The thickness of the coating will depend on thecharacteristics of the particular coating composition being used.However, it is well within the ability of one skilled in the art todetermine by routine experimentation the optimum thickness of aparticular coating required for a particular dosage form of the presentinvention.

The pharmaceutically acceptable hydrophobic material useful forpreparing an aversive agent in a substantially non-releasable formincludes a biodegradable polymer comprising a poly(lactic/glycolic acid)(“PLGA”), a polylactide, a polyglycolide, a polyanhydride, apolyorthoester, polycaprolactones, polyphosphazenes, polysaccharides,proteinaceous polymers, polyesthers, polydioxanone, polygluconate,polylactic-acid-polyethylene oxide copolymers, poly(hydroxybutyrate),polyphosphoesther or mixtures or blends of any of these.

In certain embodiments, biodegradable polymer comprises a poly(lactic/glycolic acid), a copolymer of lactic and glycolic acid, havingmolecular weight of about 2,000 to about 500,000 daltons. The ratio oflactic acid to glycolic acid is from about 100:0 to about 25:75, withthe ratio of lactic acid to glycolic acid of 65:35 being preferred.

Poly(lactic/glycolic acid) may be prepared by the procedure set forth inU.S. Pat. No. 4,293,539 (Ludwig et al.), the disclosure of which ishereby incorporated by reference in its entirety. In brief, Ludwigprepares the copolymer by condensation of lactic acid and glycolic acidin the presence of a readily removable polymerization catalyst (e.g., astrong acid ion-exchange resin such as Dowex HCR-W2-H). The amount ofcatalyst is not critical to the polymerization, but typically is fromabout 0.01 to about 20 parts by weight relative to the total weight ofcombined lactic acid and glycolic acid. The polymerization reaction maybe conducted without solvents at a temperature from about 100° C. toabout 250° C. for about 48 to about 96 hours, preferably under a reducedpressure to facilitate removal of water and by-products. Poly(lactic/glycolic acid) is then recovered by filtering the moltenreaction mixture in an organic solvent such as dichloromethane oracetone and then filtering to remove the catalyst.

Once the aversive agent in a substantially non-releasable form isprepared, it may be combined with an opioid agonist, along withconventional excipients known in the art, to prepare the oral dosageform of the present invention. It is contemplated that a bittering agentor capsaicin would be the most likely aversive agent to be included in asequestered formulation. The polymers and other ingredients above mayalso be utilized to formulate the aversive agents to slow release ordelay release as disclosed above.

In certain preferred embodiments of the invention, the oral dosage formis a capsule or a tablet. When being formulated as a tablet, theaversive agent and opioid agonist may be combined with one or moreinert, non-toxic pharmaceutical excipients which are suitable for themanufacture of tablets. Such excipients include, for example, an inertdiluent such as lactose; granulating and disintegrating agents such ascornstarch; binding agents such as starch; and lubricating agents suchas magnesium stearate.

The oral dosage form of the present invention may be formulated toprovide immediate release of the opioid agonist contained therein. Inother embodiments of the invention, however, the oral dosage formprovides sustained-release of the opioid agonist.

In certain embodiments, the oral dosage forms providing sustainedrelease of the opioid agonist may be prepared by admixing the aversiveagent in a substantially non-releasable form with the opioid agonist anddesirable pharmaceutical excipients to provide a tablet, and thencoating the tablet with a sustained-release tablet coating.

In certain embodiments of the invention, sustained release opioidagonist tablets may be prepared by admixing the substantiallynon-releasable form of an aversive agent with an aversive agent in amatrix that provides the tablets with sustained-releasing properties.

Dosage Forms

The opioid analgesic formulation in combination with one or moreaversive agents can be formulated as an immediate release formulation orcontrolled release oral formulation in any suitable tablet, coatedtablet or multiparticulate formulation known to those skilled in theart. The controlled release dosage form may include a controlled releasematerial which is incorporated into a matrix along with the opioidanalgesic. In addition, the aversive agent may be separate from thematrix, or incorporated into the matrix.

The controlled release dosage form may optionally comprise particlescontaining or comprising the opioid analgesic, wherein the particleshave diameter from about 0.1 mm to about 2.5 mm, preferably from about0.5 mm to about 2 mm. Additionally, the aversive agent may beincorporated into these particles, or may be incorporated into a tabletor capsule containing these particles. Preferably, the particles arefilm coated with a material that permits release of the opioid analgesicat a controlled rate in an environment of use. The film coat is chosenso as to achieve, in combination with the other stated properties, adesired in-vitro release rate. The controlled release coatingformulations of the present invention should be capable of producing astrong, continuous film that is smooth and elegant, capable ofsupporting pigments and other coating additives, non-toxic, inert, andtack-free.

In certain embodiments, the dosage forms of the present inventioncomprise normal release matrixes containing the opioid analgesic and theaversive agent.

Coated Beads

In certain embodiments of the present invention a hydrophobic materialis used to coat inert pharmaceutical beads such as nu panel 18/20 beadscomprising an opioid analgesic, and a plurality of the resultant solidcontrolled release beads may thereafter be placed in a gelatin capsulein an amount sufficient to provide an effective controlled release dosewhen ingested and contacted by an environmental fluid, e.g., gastricfluid or dissolution media. The one or more aversive agents may also becoated onto the beads comprising the opioid analgesic, may be preparedas separate beads and then combined in a dosage form including thecontrolled release beads comprising an opioid analgesic, or the one ormore aversive agents may be mixed in the dosage form with the controlledrelease beads comprising the opioid analgesic. In preferred embodimentswhere the opioid analgesic and the aversive agent are mixed in a capsuleas different beads, the beads have an exact or similar appearance inorder to deter an abuser from manually separating the beads prior toabuse in order to avoid the aversive substance. In tablet dosage forms,the aversive agent is preferably not included as a distinct layer whichcan be easier to separate from the active agent, although the presentinvention docs encompass these embodiments.

The controlled release bead formulations of the present invention slowlyrelease the opioid analgesic, e.g., when ingested and exposed to gastricfluids, and then to intestinal fluids. The controlled release profile ofthe formulations of the invention can be altered, for example, byvarying the amount of overcoating with the hydrophobic material,altering the manner in which a plasticizer is added to the hydrophobicmaterial, by varying the amount of plasticizer relative to hydrophobicmaterial, by the inclusion of additional ingredients or excipients, byaltering the method of manufacture, etc. The dissolution profile of theultimate product may also be modified, for example, by increasing ordecreasing the thickness of the retardant coating.

Spheroids or beads coated with an opioid analgesic are prepared, e.g.,by dissolving the opioid analgesic in water and then spraying thesolution onto a substrate, for example, nu pariel 18/20 beads, using aWuster insert. Thereafter, the one or more aversive agent is optionallyadded to the beads prior to coating. Optionally, additional ingredientsare also added prior to coating the beads in order to assist the bindingof the opioid to the beads. For example, a product which includeshydroxypropylmethylcellulose, etc. (e.g., Opadry®, commerciallyavailable from Colorcon, Inc.) may be added to the solution and thesolution mixed (e.g., for about 1 hour) prior to application of the sameonto the beads. The resultant coated substrate, in this example beads,may then be optionally overcoated with a barrier agent, to separate theopioid analgesic from the hydrophobic controlled release coating. Anexample of a suitable barrier agent is one which compriseshydroxypropylmethylcellulose. However, any film-former known in the artmay be used. It is preferred that the barrier agent does not affect thedissolution rate of the final product.

The beads may then be overcoated with an aqueous dispersion of thehydrophobic material. The aqueous dispersion of hydrophobic materialpreferably further includes an effective amount of plasticizer, e.g.triethyl citrate. Pre-formulated aqueous dispersions of ethylcellulose,such as Aquacoat® or Surelease®, may be used. If Surelease® is used, itis not necessary to separately add a plasticizer. Alternatively,pre-formulated aqueous dispersions of acrylic polymers such as Eudragit®can be used.

Plasticized hydrophobic material may be applied onto the substratecomprising the opioid analgesic by spraying using any suitable sprayequipment known in the art. In a preferred method, a Wursterfluidized-bed system is used in which an air jet, injected fromunderneath, fluidizes the core material and effects drying while theacrylic polymer coating is sprayed on. A sufficient amount of thehydrophobic material to obtain a predetermined controlled release ofsaid opioid analgesic when the coated substrate is exposed to aqueoussolutions, e.g. gastric fluid, is preferably applied, taking intoaccount the physical characteristics of the opioid analgesic, the mannerof incorporation of the plasticizer, etc. After coating with thehydrophobic material, a further overcoat of a film-former, such asOpadry®, is optionally applied to the beads. This overcoat is provided,if at all, in order to substantially reduce agglomeration of the beads.

The release of the opioid analgesic from the controlled releaseformulation of the present invention can be further influenced, i.e.,adjusted to a desired rate, by the addition of one or morerelease-modifying agents, or by providing one or more passagewaysthrough the coating. The ratio of hydrophobic material to water solublematerial is determined by, among other factors, the release raterequired and the solubility characteristics of the materials selected.

The release-modifying agents which function as pore-formers may beorganic or inorganic, and include materials that can be dissolved,extracted or leached from the coating in the environment of use. Thepore-formers may comprise one or more hydrophilic materials such ashydroxypropylmethylcellulose.

The controlled release coatings of the present invention can alsoinclude erosion-promoting agents such as starch and gums.

The controlled release coatings of the present invention can alsoinclude materials useful for making microporous lamina in theenvironment of use, such as polycarbonates comprised of linearpolyesters of carbonic acid in which carbonate groups reoccur in thepolymer chain.

The release-modifying agent may also comprise a semi-permeable polymer.

In certain preferred embodiments, the release-modifying agent isselected from hydroxypropylmethylcellulose, lactose, metal stearates,and mixtures of any of the foregoing.

The controlled release coatings of the present invention may alsoinclude an exit means comprising at least one passageway, orifice, orthe like. The passageway may be formed by such methods as thosedisclosed in U.S. Pat. Nos. 3,845,770; 3,916,889; 4,063,064; and4,088,864. The passageway can have any shape such as round, triangular,square, elliptical, irregular, etc.

Matrix Formulations

In certain embodiments of the present invention, the sustained releaseformulation is achieved via a matrix optionally having a controlledrelease coating as set forth herein. The present invention may alsoutilize a sustained release matrix that affords in-vitro dissolutionrates of the opioid analgesic within desired ranges and releases theopioid analgesic in a pH-dependent or pH-independent manner.

A non-limiting list of suitable sustained-release materials which may beincluded in a sustained-release matrix according to the inventionincludes hydrophilic and/or hydrophobic materials, such as gums,cellulose ethers, acrylic resins, protein derived materials, waxes,shellac, and oils such as hydrogenated castor oil and hydrogenatedvegetable oil. However, any pharmaceutically acceptable hydrophobic orhydrophilic sustained-release material which is capable of impartingsustained-release of the opioid analgesic may be used in accordance withthe present invention. Preferred sustained-release polymers includealkylcelluloses such as ethylcellulose, acrylic and methacrylic acidpolymers and copolymers; and cellulose ethers, especiallyhydroxyalkylcelluloses (especially hydroxypropylmethylcellulose) andcarboxyalkylcelluloses. Preferred acrylic and methacrylic acid polymersand copolymers include methyl methacrylate, methyl methacrylatecopolymers, ethoxyethyl methacrylates, ethyl acrylate, trimethylammonioethyl methacrylate, cyanoethyl methacrylate, aminoalkylmethacrylate copolymer, poly(acrylic acid), poly(methacrylic acid),methacrylic acid alkylamine copolymer, poly(methylmethacrylate),poly(methacrylicacid) (anhydride), polymethacrylate, polyacrylamide,poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers.Certain preferred embodiments utilize mixtures of any of the foregoingsustained-release materials in the matrix of the invention.

The matrix also may include a binder. In such embodiments, the binderpreferably contributes to the sustained-release of the opioid analgesicor pharmaceutically acceptable salt thereof from the sustained-releasematrix.

If an additional hydrophobic binder material is included, it ispreferably selected from natural and synthetic waxes, fatty acids, fattyalcohols, and mixtures of the same. Examples include beeswax, carnaubawax, stearic acid and stearyl alcohol. This list is not meant to beexclusive. In certain preferred embodiments, a combination of two ormore hydrophobic binder materials are included in the matrixformulations.

Preferred hydrophobic binder materials which may be used in accordancewith the present invention include digestible, long chain (C₈-C₅₀,especially C₁₂-C₄₀), substituted or unsubstituted hydrocarbons, such asfatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral andvegetable oils, natural and synthetic waxes and polyalkylene glycols.Hydrocarbons having a melting point of between 25° and 90° C. arepreferred. Of the long-chain hydrocarbon binder materials, fatty(aliphatic) alcohols are preferred in certain embodiments. The oraldosage form may contain up to 80% (by weight) of at least onedigestible, long chain hydrocarbon.

In certain embodiments, the hydrophobic binder material may comprisenatural or synthetic waxes, fatty alcohols (such as lauryl, myristyl,stearyl, cetyl or preferably cetostearyl alcohol), fatty acids,including but not limited to fatty acid esters, fatty acid glycerides(mono-, di-, and tri-glycerides), hydrogenated fats, hydrocarbons,normal waxes, stearic acid, stearyl alcohol and hydrophobic andhydrophilic materials having hydrocarbon backbones. Suitable waxesinclude, for example, beeswax, glycowax, castor wax and carnauba wax.For purposes of the present invention, a wax-like substance is definedas any material which is normally solid at room temperature and has amelting point of from about 30 to about 100° C. In certain preferredembodiments, the dosage form comprises a sustained release matrixcomprising an opioid analgesic; one or more aversive agents; and atleast one water soluble hydroxyalkyl cellulose, at least one C₁₂-C₃₆,preferably C₁₄-C₂₂, aliphatic alcohol and, optionally, at least onepolyalkylene glycol. The hydroxyalkyl cellulose is preferably a hydroxy(C₁ to C₆) alkyl cellulose, such as hydroxypropylcellulose,hydroxypropylmethylcellulose and, especially, hydroxyethyl cellulose.The amount of the at least one hydroxyalkyl cellulose in the presentoral dosage form may be determined, inter alia, by the precise rate ofopioid analgesic release required. The aliphatic alcohol may be, forexample, lauryl alcohol, myristyl alcohol or stearyl alcohol. Inparticularly preferred embodiments of the present oral dosage form,however, the at least one aliphatic alcohol is cetyl alcohol orcetostearyl alcohol. The amount of the aliphatic alcohol in the presentoral dosage form may be determined, as above, by the precise rate ofopioid analgesic release required. It may also depend on whether atleast one polyalkylene glycol is present in or absent from the oraldosage form. In the absence of at least one polyalkylene glycol, theoral dosage form preferably contains between about 20% and about 50% (bywt) of the aliphatic alcohol. When a polyalkylene glycol is present inthe oral dosage form, then the combined weight of the aliphatic alcoholand the polyalkylene glycol preferably constitutes between about 20% andabout 50% (by wt) of the total dosage form.

In one preferred embodiment, the ratio of, e.g., the at least onehydroxyalkyl cellulose or acrylic resin to the at least one aliphaticalcohol/polyalkylene glycol determines, to a considerable extent, therelease rate of the opioid analgesic from the formulation. In certainembodiments, a ratio of the hydroxyalkyl cellulose to the aliphaticalcohol/polyalkylene glycol of between 1:1 and 1:4 is preferred, with aratio of between 1:2 and 1:3 being particularly preferred.

In certain embodiments, the polyalkylene glycol may be, for example,polypropylene glycol, or polyethylene glycol which is preferred. Theaverage molecular weight of the at least one polyalkylene glycol ispreferably between 1,000 and 15,000, especially between 1,500 and12,000.

Another suitable sustained-release matrix comprises an alkylcellulose(especially ethylcellulose), a C₁₂ to C₃₅ aliphatic alcohol and,optionally, a polyalkylene glycol.

In addition to the above ingredients, a sustained-release matrix mayalso contain suitable quantities of other materials, e.g., diluents,lubricants, binders, granulating aids, and glidants that areconventional in the pharmaceutical art.

In order to facilitate the preparation of a solid, sustained-releaseoral dosage form according to this invention there is provided, in afurther aspect of the present invention, a process for the preparationof a solid, sustained-release oral dosage form according to the presentinvention comprising incorporating an opioid analgesic in asustained-release matrix. Incorporation in the matrix may be effected,for example, by:

(a) forming granules comprising at least one hydrophobic and/orhydrophilic material as set forth above (e.g., a water solublehydroxyalkyl cellulose) together with the opioid analgesic, and at leastone aversive agent;

(b) mixing the at least one hydrophobic and/or hydrophilic materialcontaining granules with at least one C₁₂-C₃₆ aliphatic alcohol, and

(c) optionally, compressing and shaping the granules.

The granules may be formed by any of the procedures well-known to thoseskilled in the art of pharmaceutical formulation. For example, in onepreferred method, the granules may be formed by wet granulating thehydroxyalkyl cellulose, opioid analgesic, and one or more aversiveagents with water. In a particularly preferred embodiment of thisprocess, the amount of water added during the wet granulation step ispreferably between 1.5 and 5 times, especially between 1.75 and 3.5times, the dry weight of the opioid analgesic. Optionally, the opioidanalgesic and/or the one or more aversive agents are addedextragranularly.

A sustained-release matrix can also be prepared by, e.g.,melt-granulation or melt-extrusion techniques. Generally,melt-granulation techniques involve melting a normally solid hydrophobicbinder material, e.g., a wax, and incorporating a powdered drug therein.To obtain a sustained release dosage form, it may be necessary toincorporate a hydrophobic sustained-release material, e.g.ethylcellulose or a water-insoluble acrylic polymer, into the molten waxhydrophobic binder material. Examples of sustained-release formulationsprepared via melt-granulation techniques are found, e.g., in U.S. Pat.No. 4,861,598.

The additional hydrophobic binder material may comprise one or morewater-insoluble wax-like thermoplastic substances possibly mixed withone or more wax-like thermoplastic substances being less hydrophobicthan said one or more water-insoluble wax-like substances. In order toachieve sustained release, the individual wax-like substances in theformulation should be substantially non-degradable and insoluble ingastrointestinal fluids during the initial release phases. Usefulwater-insoluble wax-like binder substances may be those with awater-solubility that is lower than about 1:5,000 (w/w).

The preparation of a suitable melt-extruded matrix according to thepresent invention may, for example, include the steps of blending theopioid analgesic and at least one aversive agent, together with asustained release material and preferably a binder material to obtain ahomogeneous mixture. The homogeneous mixture is then heated to atemperature sufficient to at least soften the mixture sufficiently toextrude the same. The resulting homogeneous mixture is then extruded,e.g., using a twin-screw extruder, to form strands. The extrudate ispreferably cooled and cut into multiparticulates by any means known inthe art. The matrix multiparticulates are then divided into unit doses.The extrudate preferably has a diameter of from about 0.1 to about 5 mmand provides sustained release of the opioid analgesic orpharmaceutically acceptable salt thereof for a time period of at leastabout 12 hours.

An optional process for preparing the melt extruded formulations of thepresent invention includes directly metering into an extruder ahydrophobic sustained release material, the opioid analgesic, one ormore aversive agents, and an optional binder material; heating thehomogenous mixture; extruding the homogenous mixture to thereby formstrands; cooling the strands containing the homogeneous mixture; cuttingthe strands into matrix multiparticulates having a size from about 0.1mm to about 12 mm; and dividing said particles into unit doses. In thisaspect of the invention, a relatively continuous manufacturing procedureis realized.

Optionally, the one or more aversive agents may be added to a dosageform including multiparticulates comprising opioid analgesic (withoutthe one or more aversive agents).

Plasticizers, such as those described above, may be included inmelt-extruded matrices. The plasticizer is preferably included as fromabout 0.1 to about 30% by weight of the matrix. Other pharmaceuticalexcipients, e.g., talc, mono or poly saccharides, lubricants and thelike may be included in the sustained release matrices of the presentinvention as desired. The amounts included will depend upon the desiredcharacteristic to be achieved.

The diameter of the extruder aperture or exit port can be adjusted tovary the thickness of the extruded strands. Furthermore, the exit partof the extruder need not be round; it can be oblong, rectangular, etc.The exiting strands can be reduced to particles using a hot wire cutter,guillotine, etc.

A melt extruded matrix multiparticulate system can be, for example, inthe form of granules, spheroids or pellets depending upon the extruderexit orifice. For purposes of the present invention, the terms“melt-extruded matrix multiparticulate(s)” and “melt-extruded matrixmultiparticulate system(s)” and “melt-extruded matrix particles” shallrefer to a plurality of units, preferably within a range of similar sizeand/or shape and containing one or more active agents and one or moreexcipients, preferably including a hydrophobic sustained releasematerial as described herein. Preferably the melt-extruded matrixmultiparticulates will be of a range of from about 0.1 to about 12 mm inlength and have a diameter of from about 0.1 to about 5 mm. In addition,it is to be understood that the melt-extruded matrix multiparticulatescan be any geometrical shape within this size range. In certainembodiments, the extrudate may simply be cut into desired lengths anddivided into unit doses of the therapeutically active agent without theneed of a spheronization step.

In one preferred embodiment, oral dosage forms are prepared that includean effective amount of melt-extruded matrix multiparticulates within acapsule. For example, a plurality of the melt-extruded matrixmultiparticulates may be placed in a gelatin capsule in an amountsufficient to provide an effective sustained release dose when ingestedand contacted by gastrointestinal fluid.

In another embodiment, a suitable amount of the multiparticulateextrudate is compressed into an oral tablet using conventional tabletingequipment using standard techniques. Techniques and compositions formaking tablets (compressed and molded), capsules (hard and soft gelatin)and pills are also described in Remington's Pharmaceutical Sciences,(Arthur Osol, editor), 1553-1593 (1980).

In yet another preferred embodiment, the extrudate can be shaped intotablets as set forth in U.S. Pat. No. 4,957,681 (Klimesch, et. al.).

Optionally, the sustained-release matrix multiparticulate systems,tablets, or capsules can be coated with a sustained release coating suchas the sustained release coatings described herein. Such coatingspreferably include a sufficient amount of hydrophobic and/or hydrophilicsustained-release material to obtain a weight gain level from about 2 toabout 25 percent, although the overcoat may be greater depending upon,e.g., the desired release rate. The coating can optionally contain oneor more of the aversive agents. In such embodiments, an optional secondovercoat can be applied as to minimize the perception of the aversiveagent when a dosage form of the present invention is administeredintact.

The dosage forms of the present invention may further includecombinations of melt-extruded matrix multiparticulates containing anopioid analgesic; one or more aversive agents; or mixtures thereof.Furthermore, the dosage forms can also include an amount of an immediaterelease opioid analgesic for prompt therapeutic effect. The immediaterelease opioid analgesic may be incorporated, e.g., as separatemultiparticulates within a gelatin capsule, or may be coated on thesurface of, e.g., melt extruded matrix multiparticulates.

The sustained-release profile of the melt-extruded formulations of theinvention can be altered, for example, by varying the amount ofsustained-release material, by varying the amount of plasticizerrelative to other matrix constituents, by varying the amount ofhydrophobic material, by the inclusion of additional ingredients orexcipients, by altering the method of manufacture, etc.

In other embodiments of the invention, melt-extruded formulations areprepared without the inclusion of the opioid analgesic; one or moreaversive agents; or mixtures thereof; which is added thereafter to theextrudate. Such formulations typically will have the opioid analgesic;one or more aversive agents; or mixtures thereof blended together withthe extruded matrix material, and then the mixture would be tableted inorder to provide a slow release formulation. Such formulations may beadvantageous, for example, when the opioid analgesic; one or moreaversive agents; or mixtures thereof included in the formulation issensitive to temperatures needed for softening the hydrophobic materialand/or the retardant material.

Typical melt-extrusion production systems suitable for use in accordancewith the present invention include a suitable extruder drive motorhaving variable speed and constant torque control, start-stop controls,and a meter. In addition, the production system will include atemperature control console which includes temperature sensors, coolingmeans and temperature indicators throughout the length of the extruder.In addition, the production system will include an extruder such as atwin-screw extruder which consists of two counter-rotating intermeshingscrews enclosed within a cylinder or barrel having an aperture or die atthe exit thereof. The feed materials enter through a feed hopper and aremoved through the barrel by the screws and are forced through the dieinto strands which are thereafter conveyed such as by a continuousmovable belt to allow for cooling and being directed to a pelletizer orother suitable device to render the extruded ropes into the matrixmultiparticulate system. The pelletizer can consist of rollers, fixedknife; rotating cutter and the like. Suitable instruments and systemsare available from distributors such as C.W. Brabender Instruments, Inc.of South Hackensack, N.J. Other suitable apparatus will be apparent tothose of ordinary skill in the art.

A further aspect of the invention is related to the preparation ofmelt-extruded matrix multiparticulates as set forth above in a mannerwhich controls the amount of air included in the extruded product. Bycontrolling the amount of air included in the extrudate, the releaserate of the opioid analgesic, one or more aversive agents, or mixturesthereof may be altered.

Thus, in a further aspect of the invention, the melt-extruded product isprepared in a manner which substantially excludes air during theextrusion phase of the process. This may be accomplished, for example,by using a Leistritz extruder having a vacuum attachment. The extrudedmatrix multiparticulates prepared according to the invention using theLeistritz extruder under vacuum provides a melt-extruded product havingdifferent physical characteristics. In particular, the extrudate issubstantially non-porous when magnified, e.g., using a scanning electronmicroscope which provides an SEM (scanning electron micrograph). Suchsubstantially non-porous formulations may provide a faster release ofthe therapeutically active agent, relative to the same formulationprepared without vacuum. SEMs of the matrix multiparticulates preparedusing an extruder under vacuum appear very smooth, and themultiparticulates tend to be more robust than those multiparticulatesprepared without vacuum. It has been observed that in at least certainformulations, the use of extrusion under vacuum provides an extrudedmatrix multiparticulate product which is more pH-dependent than itscounterpart formulation prepared without vacuum.

Alternatively, the melt-extruded product is prepared using aWerner-Pfleiderer twin screw extruder.

In certain embodiments, a spheronizing agent is added to a granulate ormatrix multiparticulate and then spheronized to produce sustainedrelease spheroids. The spheroids are then optionally overcoated with asustained release coating by methods such as those described above.

Spheronizing agents which may be used to prepare the matrixmultiparticulate formulations of the present invention include anyart-known spheronizing agent. Cellulose derivatives are preferred, andmicrocrystalline cellulose is especially preferred. A suitablemicrocrystalline cellulose is, for example, the material sold as AvicelPH 101 (TradeMark, FMC Corporation). The spheronizing agent ispreferably included as about 1 to about 99% of the matrixmultiparticulate by weight.

In certain embodiments, in addition to the opioid analgesic, one or moreaversive agents, and spheronizing agent, the spheroids may also containa binder. Suitable binders, such as low viscosity, water solublepolymers, will be well known to those skilled in the pharmaceutical art.However, water soluble hydroxy lower alkyl cellulose, such as hydroxypropyl cellulose, are preferred. Additionally (or alternatively) thespheroids may contain a water insoluble polymer, especially an acrylicpolymer, an acrylic copolymer, such as a methacrylic acid-ethyl acrylatecopolymer, or ethyl cellulose.

In certain embodiments, a sustained release coating is applied to thesustained release spheroids, granules, or matrix multiparticulates. Insuch embodiments, the sustained-release coating may include a waterinsoluble material such as (a) a wax, either alone or in admixture witha fatty alcohol; or (b) shellac or zein. The coating is preferablyderived from an aqueous dispersion of the hydrophobic sustained releasematerial.

In certain embodiments, it is necessary to overcoat the sustainedrelease spheroids, granules, or matrix multiparticulates comprising theopioid analgesic, one or more aversive agents, and sustained releasecarrier with a sufficient amount of the aqueous dispersion of, e.g.,alkylcellulose or acrylic polymer, to obtain a weight gain level fromabout 2 to about 50%, e.g., about 2 to about 25%, in order to obtain asustained-release formulation. The overcoat may be lesser or greaterdepending upon, e.g., the desired release rate, the inclusion ofplasticizer in the aqueous dispersion and the manner of incorporation ofthe same. Cellulosic materials and polymers, including alkylcelluloses,are sustained release materials well suited for coating the sustainedrelease spheroids, granules, or matrix multiparticulates according tothe invention. Simply by way of example, one preferred alkylcellulosicpolymer is ethylcellulose, although the artisan will appreciate thatother cellulose and/or alkylcellulose polymers may be readily employed,singly or in any combination, as all or part of a hydrophobic coatingaccording to the invention.

One commercially available aqueous dispersion of ethylcellulose isAquacoat (FMC Corp., Philadelphia, Pa., U.S.A.). Aquacoat® is preparedby dissolving the ethylcellulose in a water-immiscible organic solventand then emulsifying the same in water in the presence of a surfactantand a stabilizer. After homogenization to generate submicron droplets,the organic solvent is evaporated under vacuum to form a pseudolatex.The plasticizer is not incorporated in the pseudolatex during themanufacturing phase. Thus, prior to using the same as a coating, it isnecessary to intimately mix the Aquacoat® with a suitable plasticizerprior to use.

Another aqueous dispersion of ethylcellulose is commercially availableas Surelease® (Colorcon, Inc., West Point, Pa., U.S.A.). This product isprepared by incorporating plasticizer into the dispersion during themanufacturing process. A hot melt of a polymer, plasticizer (dibutylsebacate), and stabilizer (oleic acid) is prepared as a homogeneousmixture, which is then diluted with an alkaline solution to obtain anaqueous dispersion which can be applied directly to the sustainedrelease spheroids, granules, or matrix multiparticulates.

In other preferred embodiments of the present invention, the sustainedrelease material comprising the sustained-release coating is apharmaceutically acceptable acrylic polymer, including but not limitedto acrylic acid and methacrylic acid copolymers, methyl methacrylatecopolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate,poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamidecopolymer, poly(methyl methacrylate), polymethacrylate, poly(methylmethacrylate) copolymer, polyacrylamide, aminoalkyl methacrylatecopolymer, poly(methacrylic acid anhydride), and glycidyl methacrylatecopolymers.

In certain preferred embodiments, the acrylic polymer is comprised ofone or more ammonio methacrylate copolymers. Ammonio methacrylatecopolymers are well known in the art, and are described in the NationalFormulary (NF) XVII as fully polymerized copolymers of acrylic andmethacrylic acid esters with a low content of quaternary ammoniumgroups. In order to obtain a desirable dissolution profile, it may benecessary to incorporate two or more ammonio methacrylate copolymershaving differing physical properties, such as different molar ratios ofthe quaternary ammonium groups to the neutral (meth)acrylic esters.

Certain methacrylic acid ester-type polymers are useful for preparingpH-dependent coatings which may be used in accordance with the presentinvention. For example, there are a family of copolymers synthesizedfrom diethylaminoethyl methacrylate and other neutral methacrylicesters, also known as methacrylic acid copolymer or polymericmethacrylates, commercially available as Eudragit® from Rohm GMBH andCo. Kg Darmstadt, Germany. There are several different types ofEudragit®. For example, Eudragit E is an example of a methacrylic acidcopolymer which swells and dissolves in acidic media. Eudragit L is amethacrylic acid copolymer which does not swell at about pH<5.7 and issoluble at about pH>6. Eudragit® does not swell at about pH<6.5 and issoluble at about pH>7. Eudragit RL and Eudragit RS are water swellable,and the amount of water absorbed by these polymers is pH-dependent;however, dosage forms coated with Eudragit RL and RS are pH-independent.

In certain preferred embodiments, the acrylic coating comprises amixture of two acrylic resin lacquers commercially available from Rohmunder the Tradenames Eudragit® RL30D and Eudragit® RS30D, respectively.Eudragit® RL300 and Eudragit® RS30D are copolymers of acrylic andmethacrylic esters with a low content of quaternary ammonium groups, themolar ratio of ammonium groups to the remaining neutral (meth)acrylicesters being 1:20 in Eudragit® RL30D and 1:40 in Eudragit® RS30D. Themean molecular weight is about 150,000. The code designations RL (highpermeability) and RS (low permeability) refer to the permeabilityproperties of these agents. Eudragit® RL/RS mixtures are insoluble inwater and in digestive fluids. However, coatings formed from the sameare swellable and permeable in aqueous solutions and digestive fluids.

The Eudragit® RL/RS dispersions of the present invention may be mixedtogether in any desired ratio in order to ultimately obtain asustained-release formulation having a desirable dissolution profile.Desirable sustained-release formulations may be obtained, for instance,from a retardant coating derived from 100% Eudragit® RL, 50% Eudragit®RL and 50% Eudragit® RS, and 10% Eudragit® RL:Eudragit® 90% RS. Ofcourse, one skilled in the art will recognize that other acrylicpolymers may also be used, such as, for example, Eudragit® L. Inembodiments of the present invention where the coating comprises anaqueous dispersion of a hydrophobic sustained release material, theinclusion of an effective amount of a plasticizer in the aqueousdispersion of hydrophobic material will further improve the physicalproperties of the sustained-release coating. For example, becauseethylcellulose has a relatively high glass transition temperature anddoes not form flexible films under normal coating conditions, it ispreferable to incorporate a plasticizer into an ethylcellulose coatingcontaining sustained-release coating before using the same as a coatingmaterial. Generally, the amount of plasticizer included in a coatingsolution is based on the concentration of the film-former, e.g., mostoften from about 1 to about 50 percent by weight of the film-former.Concentration of the plasticizer, however, can only be properlydetermined after careful experimentation with the particular coatingsolution and method of application.

Examples of suitable plasticizers for ethylcellulose include waterinsoluble plasticizers such as dibutyl sebacate, diethyl phthalate,triethyl citrate, tributyl citrate, and triacetin, although it ispossible that other water-insoluble plasticizers (such as acetylatedmonoglycerides, phthalate esters, castor oil, etc.) may be used.Triethyl citrate is an especially preferred plasticizer for the aqueousdispersions of ethyl cellulose of the present invention.

Examples of suitable plasticizers for the acrylic polymers of thepresent invention include, but are not limited to citric acid esterssuch as triethyl citrate NF XVI, tributyl citrate, dibutyl phthalate,and possibly 1,2-propylene glycol. Other plasticizers which have provedto be suitable for enhancing the elasticity of the films formed fromacrylic films such as Eudragit® RL/RS lacquer solutions includepolyethylene glycols, propylene glycol, diethyl phthalate, castor oil,and triacetin. Triethyl citrate is an especially preferred plasticizerfor the aqueous dispersions of ethyl cellulose of the present invention.

In certain embodiments, the uncoated/coated sustained release spheroids,granules, or matrix multiparticulates containing the opioid analgesic;and one or more aversive agents; are cured until an endpoint is reachedat which the sustained release spheroids, granules, or matrixmultiparticulates provide a stable dissolution of the opioid. The curingendpoint may be determined by comparing the dissolution profile (curve)of the dosage form immediately after curing to the dissolution profile(curve) of the dosage form after exposure to accelerated storageconditions of, e.g., at least one month at a temperature of 40° C. and arelative humidity of 75%. Cured formulations are described in detail inU.S. Pat. Nos. 5,273,760; 5,286,493; 5,500,227; 5,580,578; 5,639,476;5,681,585; and 6,024,982. Other examples of sustained-releaseformulations and coatings which may be used in accordance with thepresent invention include those described in U.S. Pat. Nos. 5,324,351;5,356,467; and 5,472,712.

In addition to the above ingredients, the spheroids, granules, or matrixmultiparticulates may also contain suitable quantities of othermaterials, e.g., diluents, lubricants, binders, granulating aids, andglidants that are conventional in the pharmaceutical art in amounts upto about 50% by weight of the formulation if desired. The quantities ofthese additional materials will be sufficient to provide the desiredeffect to the desired formulation.

Specific examples of pharmaceutically acceptable carriers and excipientsthat may be used to formulate oral dosage forms are described in theHandbook of Pharmaceutical Excipients, American PharmaceuticalAssociation (1986), incorporated by reference herein.

It has further been found that the addition of a small amount of talc tothe sustained release coating reduces the tendency of the aqueousdispersion to stick during processing, and acts as a polishing agent.

Osmotic Dosage Forms

Sustained release dosage forms according to the present invention mayalso be prepared as osmotic dosage formulations. The osmotic dosageforms preferably include a bilayer core comprising a drug layer(containing the opioid analgesic and optionally one or more aversiveagents) and a delivery or push layer (which may contain the one or moreaversive agents), wherein the bilayer core is surrounded by asemipermeable wall and optionally having at least one passagewaydisposed therein.

The expression “passageway” as used for the purpose of this invention,includes aperture, orifice, bore, pore, porous element through which theopioid analgesic can be pumped, diffuse or migrate through a fiber,capillary tube, porous overlay, porous insert, microporous member, orporous composition. The passageway can also include a compound thaterodes or is leached from the wall in the fluid environment of use toproduce at least one passageway. Representative compounds for forming apassageway include erodible poly(glycolic) acid, or poly(lactic) acid inthe wall; a gelatinous filament; a water-removable poly(vinyl alcohol);leachable compounds such as fluid-removable pore-formingpolysaccharides, acids, salts or oxides. A passageway can be formed byleaching a compound from the wall, such as sorbitol, sucrose, lactose,maltose, or fructose, to form a sustained-release dimensionalpore-passageway. The passageway can have any shape, such as round,triangular, square and elliptical, for assisting in the sustainedmetered release of opioid analgesic from the dosage form. The dosageform can be manufactured with one or more passageways in spaced-apartrelation on one or more surfaces of the dosage form. A passageway andequipment for forming a passageway are described in U.S. Pat. Nos.3,845,770; 3,916,899; 4,063,064 and 4,088,864. Passageways comprisingsustained-release dimensions sized, shaped and adapted as areleasing-pore formed by aqueous leaching to provide a releasing-pore ofa sustained-release rate are described in U.S. Pat. Nos. 4,200,098 and4,285,987.

In certain embodiments, the bilayer core comprises a drug layer withopioid analgesic and a displacement or push layer optionally containingthe one or more aversive agents. The one or more aversive agents mayoptionally be included in the drug layer instead of or in addition tobeing included in the push layer. In certain embodiments the drug layermay also comprise at least one polymer hydrogel. The polymer hydrogelmay have an average molecular weight of between about 500 and about6,000,000. Examples of polymer hydrogels include but are not limited toa maltodextrin polymer comprising the formula (C₆H₁₂O₅)_(n).H₂O, whereinn is 3 to 7,500, and the maltodextrin polymer comprises a 500 to1,250,000 number-average molecular weight; a poly(alkylene oxide)represented by, e.g., a poly(ethylene oxide) and a poly(propylene oxide)having a 50,000 to 750,000 weight-average molecular weight, and morespecifically represented by a poly(ethylene oxide) of at least one of100,000, 200,000, 300,000 or 400,000 weight-average molecular weights;an alkali carboxyalkylcellulose, wherein the alkali is sodium orpotassium, the alkyl is methyl, ethyl, propyl, or butyl of 10,000 to175,000 weight-average molecular weight; and a copolymer ofethylene-acrylic acid, including methacrylic and ethacrylic acid of10,000 to 500,000 number-average molecular weight.

In certain embodiments of the present invention, the delivery or pushlayer comprises an osmopolymer. Examples of an osmopolymer include butare not limited to a member selected from the group consisting of apolyalkylene oxide and a carboxyalkylcellulose. The polyalkylene oxidepossesses a 1,000,000 to Ser. No. 10/000,000 weight-average molecularweight. The polyalkylene oxide may be a member selected from the groupconsisting of polymethylene oxide, polyethylene oxide, polypropyleneoxide, polyethylene oxide having a 1,000,000 average molecular weight,polyethylene oxide comprising a 5,000,000 average molecular weight,polyethylene oxide comprising a 7,000,000 average molecular weight,cross-linked polymethylene oxide possessing a 1,000,000 averagemolecular weight, and polypropylene oxide of 1,200,000 average molecularweight. Typical osmopolymer carboxyalkylcellulose comprises a memberselected from the group consisting of alkali carboxyalkylcellulose,sodium carboxymethylcellulose, potassium carboxymethylcellulose, sodiumcarboxyethylcellulose, lithium carboxymethylcellulose, sodiumcarboxyethylcellulose, carboxyalkylhydroxyalkylcellulose, carboxymethylhydroxyethyl cellulose, carboxyethylhydroxyethylcellulose andcarboxymethylhydroxypropylcellulose. The osmopolymers used for thedisplacement layer exhibit an osmotic pressure gradient across thesemipermeable wall. The osmopolymers imbibe fluid into dosage form,thereby swelling and expanding as an osmotic hydrogel (also known asosmogel), whereby they push the contents of the drug layer from theosmotic dosage form.

The push layer may also include one or more osmotically effectivecompounds also known as osmagents and as osmotically effective solutes.They imbibe an environmental fluid, for example, from thegastrointestinal tract, into dosage form and contribute to the deliverykinetics of the displacement layer. Examples of osmotically activecompounds comprise a member selected from the group consisting ofosmotic salts and osmotic carbohydrates. Examples of specific osmagentsinclude but are not limited to sodium chloride, potassium chloride,magnesium sulfate, lithium phosphate, lithium chloride, sodiumphosphate, potassium sulfate, sodium sulfate, potassium phosphate,glucose, fructose and maltose.

The push layer may optionally include a hydroxypropylalkylcellulosepossessing a 9,000 to 450,000 number-average molecular weight. Thehydroxypropylalkylcellulose is represented by a member selected from thegroup consisting of hydroxypropylmethylcellulose,hydroxypropylethylcellulose, hydroxypropyl isopropyl cellulose,hydroxypropylbutylcellulose, and hydroxypropyl pentyl cellulose.

The push layer may also optionally comprise an antioxidant to inhibitthe oxidation of ingredients. Some examples of antioxidants include butare not limited to a member selected from the group consisting ofascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, a mixtureof 2 and 3 tertiary-butyl-4-hydroxyanisole, butylated hydroxytoluene,sodium isoascorbate, dihydroguaretic acid, potassium sorbate, sodiumbisulfate, sodium metabisulfate, sorbic acid, potassium ascorbate,vitamin E, 4-chloro-2,6-ditertiary butylphenol, alphatocopherol, andpropylgallate.

In certain alternative embodiments, the dosage form comprises asubstantially homogenous core comprising opioid analgesic, one or moreaversive agents, a pharmaceutically acceptable polymer (e.g.,polyethylene oxide), optionally a disintegrant (e.g.,polyvinylpyrrolidone), optionally an absorption enhancer (e.g., a fattyacid, a surfactant, a chelating agent, a bile salt, etc.). Thesubstantially homogenous core is surrounded by a semipermeable wallhaving a passageway (as defined above) for the release of the opioidanalgesic, and the one or more aversive agents.

In certain embodiments, the semipermeable wall comprises a memberselected from the group consisting of a cellulose ester polymer, acellulose ether polymer and a cellulose ester-ether polymer.Representative wall polymers comprise a member selected from the groupconsisting of cellulose acylate, cellulose diacylate, cellulosetriacylate, cellulose acetate, cellulose diacetate, cellulosetriacetate, mono-, di- and tricellulose alkenylates, and mono-, di- andtricellulose alkinylates. The poly(cellulose) used for the Presentinvention comprises a number-average molecular weight of 20,000 to7,500,000.

Additional semipermeable polymers for the purpose of this inventioncomprise acetaldehyde dimethycellulose acetate, cellulose acetateethylcarbamate, cellulose acetate methylcarbamate, cellulose diacetate,propylcarbamate, cellulose acetate diethylaminoacetate; semipermeablepolyamide; semipermeable polyurethane; semipermeable sulfonatedpolystyrene; semipermeable cross-linked polymer formed by thecoprecipitation of a polyanion and a polycation as disclosed in U.S.Pat. Nos. 3,173,876; 3,276,586; 3,541,005; 3,541,006 and 3,546,876;semipermeable polymers as disclosed by Loeb and Sourirajan in U.S. Pat.No. 3,133,132; semipermeable crosslinked polystyrenes; semipermeablecross-linked poly(sodium styrene sulfonate); semipermeable crosslinkedpoly(vinylbenzyltrimethyl ammonium chloride); and semipermeable polymerspossessing a fluid permeability of 2.5×10⁻⁸ to 2.5×10⁻²(cm.sup.2/hr·atm) expressed per atmosphere of hydrostatic or osmoticpressure difference across the semipermeable wall. Other polymers usefulin the present invention are known in the art in U.S. Pat. Nos.3,845,770; 3,916,899 and 4,160,020; and in Handbook of Common Polymers,Scott, J. R. and W. J. Roff, 1971, CRC Press, Cleveland, Ohio.

In certain embodiments, preferably the semipermeable wall is nontoxic,inert, and it maintains its physical and chemical integrity during thedispensing life of the drug. In certain embodiments, the dosage formcomprises a binder. An example of a binder includes, but is not limitedto a therapeutically acceptable vinyl polymer having a 5,000 to 350,000viscosity-average molecular weight, represented by a member selectedfrom the group consisting of poly-n-vinylamide, poly-n-vinyl acetamide,poly(vinyl pyrrolidone), also known as poly-n-vinylpyrrolidone,poly-n-vinylcaprolactone, poly-n-vinyl-5-methyl-2-pyrrolidone, andpoly-n-vinyl-pyrrolidone copolymers with a member selected from thegroup consisting of vinyl acetate, vinyl alcohol, vinyl chloride, vinylfluoride, vinyl butyrate, vinyl laureate, and vinyl stearate. Otherbinders include for example, acacia, starch, gelatin, andhydroxypropylalkylcellulose of 9,200 to 250,000 average molecularweight.

In certain embodiments, the dosage form comprises a lubricant, which maybe used during the manufacture of the dosage form to prevent sticking todie wall or punch faces. Examples of lubricants include but are notlimited to magnesium stearate, sodium stearate, stearic acid, calciumstearate, magnesium oleate, oleic acid, potassium oleate, caprylic acid,sodium stearyl fumarate, and magnesium palmitate.

Transdermal Delivery Systems

The formulations of the present invention may be formulated as atransdermal delivery system, such as transdermal patches. In certainembodiments of the present invention, a transdermal patch comprises anopioid agonist contained in a reservoir or a matrix, and an adhesivewhich allows the transdermal device to adhere to the skin, allowing thepassage of the active agent from the transdermal device through the skinof the patient, with the inclusion of the aversive agents as disclosedherein which are not releasable when the dosage form is administeredintact but which are releasable when the dosage form is broken ortampered with in order to release the opioid from the transdermalsystem.

Transdermal delivery system providing a controlled-release of an opioidagonist is known. For example, Duragesic® patch (commercially availablefrom Janssen Pharmaceutical) contains an opioid agonist (fentanyl) andis said to provide adequate analgesia for up to 48 to 72 hours (2 to 3days). This formulation can be reformulated with an aversive agent asdisclosed herein.

There are several types of transdermal formulations of buprenorphinereported in the literature. See, for example, U.S. Pat. No. 5,240,711(Hille et al.), U.S. Pat. No. 5,225,199 (Hidaka et al.), U.S. Pat. No.5,069,909 (Sharma et al.), U.S. Pat. No. 4,806,341 (Chien et al.), andU.S. Pat. No. 5,026,556 (Drust et al.), all of which are herebyincorporated by reference. These transdermal devices can also bereformulated with the aversive agents as disclosed herein.

The transdermal delivery system used in the present invention may alsobe prepared in accordance with U.S. Pat. No. 5,069,909 (Sharma et al.),hereby incorporated by reference. This patent describes a laminatedcomposite for administering buprenorphine transdermally to treat pain.The transdermal delivery system used in the present invention may alsobe prepared in accordance with U.S. Pat. No. 4,806,341 (Chien et al.),hereby incorporated by reference. This patent describes a transdermalmorphinan narcotic analgesic or antagonist (including buprenorphine)pharmaceutical polymer matrix dosage unit having a backing layer whichis substantially impervious to the buprenorphine, and a polymer matrixdisc layer which is adhered to the backing layer and which hasmicrodisposed therein effective dosage amounts of the buprenorphine.

The transdermal delivery system used in the present invention may alsobe that described in U.S. Pat. No. 5,026,556 (Drust et al.), herebyincorporated by reference. Therein, compositions for the transdermaldelivery of buprenorphine comprise buprenorphine in a carrier of a polarsolvent material selected from the group consisting of C₃-C₄ diols,C₃-C₆ triols, and mixtures thereof, and a polar lipid material selectedfrom the group consisting of fatty alcohol esters, fatty acid esters,and mixtures thereof; wherein the polar solvent material and the lipidmaterial are present in a weight ratio of solvent material:lipidmaterial of from 60:40 to about 99:1. The transdermal delivery systemused in the present invention may also be that described in U.S. Pat.No. 4,588,580 (Gale, et al.), hereby incorporated by reference. Thatsystem comprises a reservoir for the drug having a skin proximal,material releasing surface area in the range of about 5-100 cm² andcontaining between 0.1 and 50% by weight of a skin permeable form of thebuprenorphine. The reservoir contains an aqueous gel comprising up toabout 47-95% ethanol, 1-10% gelling agent, 0.1-10% buprenorphine, andrelease rate controlling means disposed in the flow path of the drug tothe skin which limits the flux of the buprenorphine from the systemthrough the skin.

The transdermal delivery system used in the present invention may alsobe that described in PCT/US01/04347 to Oshlack et al.

The present invention is contemplated to encompass all transdermalformulations, e.g., the technologies described above, with the inclusionof an aversive agent, such that the dosage form deters abuse of theopioid therein.

The aversive agent in non-releasable form when administered intact canbe formulated in accordance with U.S. Pat. No. 5,149,538 to Granger,hereby incorporated by reference. Alternatively, the aversive agent andthe opioid agonist can be separated from the opioid by a layer whichbecomes disrupted when the dosage form is tampered with, thereby mixingthe aversive agent with the opioid agonist. Alternatively, a combinationof both systems can be used.

Suppositories

The controlled release formulations of the present invention may beformulated as a pharmaceutical suppository for rectal administrationcomprising an opioid analgesic, and at least one aversive agent in acontrolled release matrix, and a suppository vehicle (base). Preparationof controlled release suppository formulations is described in, e.g.,U.S. Pat. No. 5,215,758.

The suppository base chosen should be compatible with the agent(s) ofthe present invention. Further, the suppository base is preferablynon-toxic and nonirritating to mucous membranes, melts or dissolves inrectal fluids, and is stable during storage.

In certain preferred embodiments of the present invention for bothwater-soluble and water-insoluble drugs, the suppository base comprisesa fatty acid wax selected from the group consisting of mono-, di- andtriglycerides of saturated, natural fatty acids of the chain length C₁₂to C₁₈.

In preparing the suppositories of the present invention other excipientsmay be used. For example, a wax may be used to form the proper shape foradministration via the rectal route. This system can also be usedwithout wax, but with the addition of diluent filled in a gelatincapsule for both rectal and oral administration.

Examples of suitable commercially available mono-, di- and triglyceridesinclude saturated natural fatty acids of the 12-18 carbon atom chainsold under the trade name Novata™ (types AB, AB, B, BC, BD, BBC, E, BCF,C, D and 299), manufactured by Henkel, and Witepsol™ (types H5, H12,H15, H175, H185, H19, H32, H35, H39, H42, W25, W31, W35, W45, S55, S58,E75, E76 and E85), manufactured by Dynamit Nobel.

Other pharmaceutically acceptable suppository bases may be substitutedin whole or in part for the above-mentioned mono-, di- andtriglycerides. The amount of base in the suppository is determined bythe size (i.e. actual weight) of the dosage form, the amount of base(e.g., alginate) and drug used. Generally, the amount of suppositorybase is from about 20 percent to about 90 percent by weight of the totalweight of the suppository. Preferably, the amount of base in thesuppository is from about 65 percent to about 80 percent, by weight ofthe total weight of the suppository.

In certain embodiments of the dosage forms of the present invention mayalso include a surfactant. Surfactants useful in accordance with thepresent invention, include for example, ionic and nonionic surfactantsor wetting agents commonly used in the formulation of pharmaceuticals,including but not limited to castor oil derivatives, cholesterol,polyglycolyzed glycerides, acetylated monoglycerides, sorbitan fattyacid esters, poloxamers, polysorbates, polyoxyethylene sorbitan fattyacid esters, polyoxyethylene compounds, monoglycerides or ethoxylatedderivatives thereof, diglycerides or polyoxyethylene derivativesthereof, sodium docusate, sodium laurylsulfate, cholic acid orderivatives thereof, ethoxylated alcohols, ethoxylated esters,ethoxylated amides, polyoxypropylene compounds, propoxylated alcohols,ethoxylated/propoxylated block polymers, propoxylated esters,alkanolamides, amine oxides, fatty acid esters of polyhydric alcohols,ethylene glycol esters, diethylene glycol esters, propylene glycolesters, glycerol esters, polyglycerol fatty acid esters, SPAN's (e.g.,sorbitan esters), TWEEN's (i.e., sucrose esters), glucose (dextrose)esters, alkali metal sulfates, quaternary ammonium compounds,amidoamines, and aminimides, simethicone, lecithins, alcohols,phospholipids, and mixtures thereof

Mixed surfactant/wetting agents useful in accordance with the presentinvention include, for example, sodium lauryl sulfate/polyethyleneglycol (PEG) 6000 and sodium lauryl sulfate/PEG 6000/stearic acid, etc.

In certain embodiments of the present invention, the dosage form mayalso include an emulsifying agent. Emulsifying agents useful inaccordance with the present invention include, for example,monoglycerides, sucrose/fatty acid esters, polyglycerol/fatty acidesters, sorbitan/fatty acid esters, lecithins, potassium and sodiumsalts of rosin acids and higher fatty acids, as well as sulfates andsulfonates of these acids, amine salts of hydroxylamines of long-chainfatty acid esters, quaternary ammonium salts such asstearyl-dimethylbenzylammonium chloride andtridecylbenzenehydroxyethylimidazole chloride, phosphoric esters ofhigher alcohols such as capryl and octyl alcohol, and monoesters ofoleic acid and pentaerythritol such as sorbitan monooleates, andmixtures thereof

The oral dosage form and methods for use of the present invention mayfurther include, in addition to an opioid analgesic and at least oneaversive agent, one or more drugs that may or may not actsynergistically with the opioid analgesic. Thus, in certain embodiments,a combination of two opioid analgesics may be included in the dosageform. For example, the dosage form may include two opioid analgesicshaving different properties, such as half-life, solubility, potency, anda combination of any of the foregoing.

In yet further embodiments, one or more opioid analgesic is included anda further non-opioid drug is also included. Such non-opioid drugs wouldpreferably provide additional analgesia, and include, for example,aspirin, acetaminophen; non-steroidal anti-inflammatory drugs(“NSAIDS”), e.g., ibuprofen, ketoprofen, etc.; N-methyl-D-aspartate(NMDA) receptor antagonists, e.g., a morphinan such as dextromethorphanor dextrorphan, or ketamine; cyclooxygenase-II inhibitors (“COX-IIinhibitors”); and/or glycine receptor antagonists.

In certain preferred embodiments of the present invention, the inventionallows for the use of lower doses of the opioid analgesic by virtue ofthe inclusion of an additional non-opioid analgesic, such as an NSAID ora COX-2 inhibitor. By using lower amounts of either or both drugs, theside effects associated with effective pain management in humans arereduced.

Suitable non-steroidal anti-inflammatory agents, including ibuprofen,diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen,ketoprofen, indoprofen, piro-profen, carprofen, oxaprozin, pramoprofen,muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid,fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac,tiopinac, zidornetacin, acemetacin, fentiazac, clidanac, oxpinac,mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid,tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam orisoxicam, and the like. Useful dosages of these drugs are well known tothose skilled in the art.

N-methyl-D-aspartate (NMDA) receptor antagonists are well known in theart, and encompass, for example, morphinans such as dextromethorphan ordextrorphan, ketamine, or pharmaceutically acceptable salts thereof. Forpurposes of the present invention, the term “NMDA antagonist” is alsodeemed to encompass drugs that block a major intracellular consequenceof NMDA-receptor activation, e.g. a ganglioside such as GM₁ or GT_(1b) aphenothiazine such as trifluoperazine or a naphthalenesulfonamide suchas N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide. These drugs arestated to inhibit the development of tolerance to and/or dependence onaddictive drugs, e.g., narcotic analgesics such as morphine, codeine,etc. in U.S. Pat. Nos. 5,321,012 and 5,556,838 (both to Mayer, et al.),and to treat chronic pain in U.S. Pat. No. 5,502,058 (Mayer, et al.),all of which are hereby incorporated by reference. The NMDA antagonistmay be included alone, or in combination with a local anesthetic such aslidocaine, as described in these Mayer, et. al. patents.

The treatment of chronic pain via the use of glycine receptorantagonists and the identification of such drugs is described in U.S.Pat. No. 5,514,680 (Weber, et al.).

COX-2 inhibitors have been reported in the art and many chemicalstructures are known to produce inhibition of cyclooxygenase-2. COX-2inhibitors are described, for example, in U.S. Pat. Nos. 5,616,601;5,604,260; 5,593,994; 5,550,142; 5,536,752; 5,521,213; 5,474,995;5,639,780; 5,604,253; 5,552,422; 5,510,368; 5,436,265; 5,409,944; and5,130,311, all of which are hereby incorporated by reference. Certainpreferred COX-2 inhibitors include celecoxib (SC-58635), DUP-697,flosulide (CGP-28238), meloxicam, 6-methoxy-2 naphthylacetic acid(6-MNA), MK-966 (also known as Vioxx), nabumetone (prodrug for 6-MNA),nimesulide, NS-398, SC-5766, SC-58215, T-614; or combinations thereof.Dosage levels of COX-2 inhibitor on the order of from about 0.005 mg toabout 140 mg per kilogram of body weight per clay are therapeuticallyeffective in combination with an opioid analgesic. Alternatively, about0.25 mg to about 7 g per patient per day of a COX-2 inhibitor isadministered in combination with an opioid analgesic.

In yet further embodiments, a non-opioid drug can be included whichprovides a desired effect other than analgesia, e.g., antitussive,expectorant, decongestant, antihistamine drugs, local anesthetics, andthe like.

The invention disclosed herein is meant to encompass the use of anypharmaceutically acceptable salts thereof of the disclosed opioidanalgesics. The pharmaceutically acceptable salts include, but are notlimited to, metal salts such as sodium salt, potassium salt, secium saltand the like; alkaline earth metals such as calcium salt, magnesium saltand the like; organic amine salts such as triethylamine salt, pyridinesalt, picoline salt, ethanolamine salt, triethanolamine salt,dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt and the like;inorganic acid salts such as hydrochloride, hydrobromide, sulfate,phosphate and the like; organic acid salts such as formate, acetate,trifluoroacetate, maleate, tartrate and the like; sulfonates such asmethanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like;amino acid salts such as arginate, asparginate, glutamate and the like.

Some of the opioid analgesics disclosed herein may contain one or moreasymmetric centers and may thus give rise to enantiomers, diastereomers,and other stereoisomeric forms. The present invention is also meant toencompass the use of any such possible forms as well as their racemicand resolved forms and mixtures thereof. When the compounds describedherein contain olefinic double bonds or other centers of geometricasymmetry, and unless specified otherwise, it is intended to includeboth E and Z geometric isomers. The use of all tautomers are intended tobe encompassed by the present invention as well.

The oral dosage forms of the present invention may be in the form oftablets, troches, lozenges, powders or granules, hard or soft capsules,microparticles (e.g., microcapsules, microspheres and the like), buccaltablets, etc.

In certain embodiments, the present invention provides for a method ofpreventing abuse of an oral controlled release dosage form of an opioidanalgesic comprising preparing the dosage forms as described above.

In certain embodiments, the present invention provides for a method ofpreventing diversion of an oral controlled release dosage form of anopioid analgesic comprising preparing the dosage forms as describedabove.

In certain embodiments, the present invention provides for a method oftreating pain while at the same time reducing the risk of abuse byadministering to a human patient the dosage forms described above.

As previously disclosed, the aversive agents of the present inventioncan be used for other drugs which can be the subject of abuse. Opioids,e.g., oxycodone are the preferred embodiments of the invention. However,it is contemplated that all of the disclosure herein With respect toopioid formulations containing the aversive agent(s) can be applied toformulations containing drugs of abuse other than opioids.

The following examples illustrate various aspects of the presentinvention. They are not to be construed to limit the claims in anymanner whatsoever.

Example 1 A 20 mg Oxycodone Formulation was Prepared Containing XanthanGum as the Aversive Agent

In this example, a small amount of xanthan gum is added to the oxycodoneformulation during the granulation process. Other gelling agents such ascurdlan, carrageenan, alginates, pectin, gelatin, furcelleran, agar,guar locust bean gum, tara gum, tragacanth, acacia, glucomannans,karaya, starch and starch derivatives, egg white powder, lacto albumin,soy protein, Jargel, gellan gum, welan gum, rhamsan gum, and the like,could also be used as gelling agents. Other semi-synthetic materialssuch as chitosan, pullulan, polylaevulan, hydroxypropyl cellulose,methylcellulose, hydroxypropylmethyl cellulose, carboxymethyl celluloseethylhydroxyethyl cellulose, all ether derivatives of cellulose, and thelike, could also be used as alternate gelling materials.

TABLE 1 Ingredients Amt/Unit (mg) Amount/Batch (gm) Oxycodone HCl 20.0209.6* Spray Dried Lactose 59.25 592.5 Povidone 5.0 50.0 Eudragit RS30D(solids) 10.0 100 Triacetin 2.0 20.0 Xanthan gum 9.0 90.0 StearylAlcohol 25.0 250.0 Talc 2.5 25.0 Magnesium Stearate 1.25 12.5 OpadryPink Y-S-14518A 5.0 50.0 *adjusted for 99.6% assay and 4.2% residualmoisture.

Process

-   1. Dispersion: Disperse Eudragit and Triacetin in an aqueous medium    to form a Eudragit/Triacetin dispersion.-   2. Granulation: Spray the Eudragit/Triacetin dispersion onto the    oxycodone HCl, Spray Dried Lactose, xanthan gum and Povidone using a    fluid bed granulator.-   3. Milling: Discharge the granulation and pass through a mill.-   4. Waxing: Melt the stearyl alcohol and add to the milled    granulation using a mixer. Allow to cool.-   5. Milling: Pass the cooled granulation through a mill.-   6. Lubrication: Lubricate the granulation with talc and magnesium    stearate using a mixer.-   7. Compression: Compress the granulation into tablets using a tablet    press.

Example 2 A 40 mg Oxycodone Formulation was Prepared Containing XanthanGum as the Aversive Agent

To determine the effect of varying amount of xanthan gum on the gellingproperty and dissolution rate of an oxycodone tablet, three levels ofxanthan gum were added to 40 mg oxycodone granulation and compressedinto tablets. Oxycodone recovery from water extraction of the tablet andthe drug release rate was determined. The oxycodone granulationformulation of Example 2 is listed in Table 2 below.

TABLE 2 Ingredients Amt/Unit (mg) Oxycodone HCl 40.0 Spray Dried Lactose39.25 Povidone 5.0 Eudragit RS30D (solids) 10.0 Triacetin 2.0 StearylAlcohol 25.0 Talc 2.5 Magnesium Stearate 1.25 Total 125

Example 2A to 2C were prepared adding different amounts (3 mg, 5 mg, and9 mg) of xanthan gum to a 125 mg oxycodone granulation of Example 2.

Example 2A

Ingredients Amt/Unit (mg) Oxycodone granulation 125 Xanthan gum 3 Total128

Example 2B

Ingredients Amt/Unit (mg) Oxycodone granulation 125 Xanthan gum 5 Total130

Example 2C

Ingredients Amt/Unit (mg) Oxycodone granulation 125 Xanthan gum 9 Total134

Process

-   1. Dispersion: Disperse Eudragit and Triacetin in an aqueous medium    to form an Eudragit/Tracetin dispersion.-   2. Granulation: Spray the Eudragit/Triacetin dispersion onto the    Oxycodone HCl, Spray Dried Lactose and Povidone using a fluid bed    granulator.-   3. Milling: Discharge the granulation and pass through a mill.-   4. Waxing: Melt the stearyl alcohol and add to the milled    granulation using a mixer. Allow to cool.-   5. Milling: Pass the cooled granulation through a mill.-   6. Lubrication: Lubricate the granulation with talc and magnesium    stearate using a mixer.-   7. Add xanthan gum (3 levels) to the granulation and mix well.-   8. Compression: Compress the granulation into tablets using a tablet    press.

Example 3

A thickening agent, citrus pectin, was added to a placebo Oxycontin® 10mg tablet (tablet without the drug present) and small amounts of water(e.g., 1 ml, 2 ml, and 3 ml) were added. The following results wereobtained and compared and listed in Table 3:

TABLE 3 Formation of gel at different concentrations (Water, pectin andOxycontin ® 10 mg placebo Tablet) Weight of Extraction ExtractionExtraction Pectin (mg) Volume (1 ml) Volume (2 ml) Volume (3 ml) 25THICK THICK THICK (55 cP) (34 cP) (24 cP) 50 THICKEST THICKER THICK (375cP) (84 cP) (42 cP) 75 THICKEST THICKEST THICKER (1830 cP) (154 cP) (94cP) THIN (less than 10 cP): The solution can be filled into a syringeTHICK (10 cP to 60 cP): Although a syringe can be filled with thissolution, it was hard to do. THICKER (60 cP to 120 cP): Syringe cannotbe filled without picking up large pockets of air. THICKEST (120 cP orgreater, e.g., up to 2000 cP or up to 5000 cP): The solution cannot beinjected or is very difficult to draw into a syringe or to inject.

The results summarized in Table 3 indicate that all the extracts werehard or difficult to pull into an insulin syringe. The pectin can alsoemulsify the excipients in the aqueous mixture making their filtrationdifficult. The tablet's coating is suspended in the mixture resembling apaste. All the samples have a creamy texture and milk like color.Additionally, the filtration with cotton cannot remove the suspendedmaterial, thus the mixture would not appeal to an addict.

This experiment shows that an ingredient, such as pectin, could be addedto the Oxycontin® Tablets to make the extraction of the oxycodone moredifficult and thus reducing the potential for abuse. Addition of pectinto the tablets appears to make the extraction extremely difficult.

Example 4

In Example 4, controlled release tablets containing an opioid agonist(oxycodone HCl) and gelling agent (microcrystalline cellulose) areprepared. The controlled release tablets comprise granulates comprisingthe opioid agonist and the gelling agent dispersed in a controlledrelease matrix. The granulates are combined with melted wax (stearylalcohol) to produce waxed granulates, which are then milled and mixedwith other excipients and compressed into tablets.

TABLE 4 Ingredient Amt/unit (mg) Amt/batch (kg) Oxycodone HCl 10.0011.00 Microcrystalline Cellulose 200.00 220.00 Spray Dried Lactose 68.7575.62 Povidone 5.00 5.50 Triacetin 2.00 2.20 Stearyl Alcohol 25.00 27.50Talc 2.50 2.75 Magnesium Stearate 1.25 1.38 Opadry White 5.00 5.50Purified Water 31.16* Total 319.50 382.61 *Remains in product asresidual moisture only.

Process:

-   1. Granulation Place Oxycodone HCl, Spray Dried Lactose, water,    Povidone, Microcrystalline Cellulose, and Triacetin into a fluid bed    granulator.    -   2. Milling Pass the granulation through a rotating impeller        mill.    -   3. Drying Dry granulation if moisture content is too high.    -   4. Waxing Melt Stearyl Alcohol and wax the above granulation by        adding melted Stearyl Alcohol onto granulation while mixing.    -   5. Cooling Cool the waxed granulation in a fluid bed dryer.    -   6. Milling Pass the cooled waxed granulation through a rotating        impeller mill.    -   7. Blending Blend the milled waxed granulation, Talc and        Magnesium Stearate.    -   8. Compression Compress the resultant granulation using a tablet        press.    -   9. Coating Prepare a film coating solution by dispersing the        Opadry in Purified Water and applying it to the tablet cores.

Example 5

In Example 5, controlled release tablets containing a opioid agonist(morphine sulfate) and gelling agent (hydroxyethyl cellulose) areprepared. The controlled release tablets comprise granulates comprisingthe opioid agonist and the gelling agent in a controlled-release matrix.The granulates are combined with melted wax (cetostearyl alcohol) toproduce waxed granulates, which are then milled and mixed with otherexcipients and compressed into tablets.

TABLE 5 Ingredient Amt/unit (mg) Amt/batch (kg) Morphine Sulfate(pentahydrate) 30.00 108.0 Spray Dried Lactose 69.5 250.2 HydroxyethylCellulose 600.0 2160.0 Purified Water 75.9* Cetostearyl Alcohol 35.0126.0 Talc 3.0 10.8 Magnesium Stearate 2.0 7.2 Opadry Purple 3.0 10.8Purified Water 61.2* Total 742.50 2673 *Remains in product as residualmoisture only.

Process:

-   -   1. Granulation Place Morphine Sulfate, Spray Dried Lactose,        water, and Hydroxyethyl Cellulose in a mixer and granulate.    -   2. Drying Dry the above granulation in a fluid bed dryer.    -   3. Milling Pass the granulation through a mill.    -   4. Drying Dry granulation if moisture content is too high.    -   5. Waxing Melt Cetostearyl Alcohol and wax the above granulation        by adding melted Cetostearyl Alcohol onto granulation while        mixing.    -   6. Cooling Cool the waxed granulation in a fluid bed dryer.    -   7. Milling Pass the cooled waxed granulation through a mill.    -   8. Blending Blend the milled waxed granulation, Talc and        Magnesium Stearate.    -   9. Compression Compress the resultant granulation using a tablet        press.    -   10. Coating Prepare a film coating solution by dispersing the        Opadry in Purified Water and applying it to the tablet cores.

In Examples 6-8, 10 mg oxycodone HCL tablets are prepared as follows:

Example 6

A controlled release tablet having the formula listed below is preparedby wet granulating oxycodone hydrochloride (25.00 gm) with lactosemonohydrate (417.5 gm), and hydroxyethyl cellulose (100.00 gm). Thegranules are sieved through a 12 mesh screen. The granules are thendried in a fluid bed dryer at 50E C and sieved through a 16 mesh screen.

Molten cetostearyl alcohol (300.0 gm) is added to the warmed oxycodonecontaining granules, and the whole was mixed thoroughly. The mixture isallowed to cool in the air, regranulated and sieved through a 16 meshscreen.

Purified Talc (15.0 gm), magnesium stearate (7.5 gm), and pectin (62.5gm) are then added and mixed with the granules. The granules are thencompressed into tablets.

TABLE 6 Ingredient Amt/unit (mg) Amt/batch (g) Oxycodone HCl 10.00 25.0Lactose Monohydrate 167.00 417.5 Hydroxyethylcellulose 40.00 100.0Cetostearyl alcohol 120.00 300.0 Talc 6.0 15.0 Magnesium Stearate 3.07.5 Pectin 25.00 62.5

Example 7

A controlled release tablet containing 10 mg of oxycodone and 50.00 mgof pectin and having the following formula is prepared in the samemanner as in Example 6:

TABLE 7 Ingredient Amt/unit (mg) Amt/batch (g) Oxycodone HCl 10.00 25.0Lactose Monohydrate 167.00 417.5 Hydroxyethylcellulose 40.00 100.0Cetostearyl alcohol 120.00 300.0 Talc 6.0 15.0 Magnesium Stearate 3.07.5 Pectin 50.00 125.00

Example 8

A controlled release tablet containing 10 mg of oxycodone and 75.00 mgof pectin and having the following formula is prepared as in Example 6:

TABLE 8 Ingredient Amt/unit (mg) Amt/batch (g) Oxycodone HCl 10.00 25.0Lactose Monohydrate 167.00 417.5 Hydroxyethylcellulose 40.00 100.0Cetostearyl alcohol 120.00 300.0 Talc 6.0 15.0 Magnesium Stearate 3.07.5 Pectin 75.00 187.5

Example 9 A 20 mg Oxycodone Formulation Containing a Bittering Agent isPrepared

In this example, a small amount of denatonium benzoate is added to anoxycodone formulation during the granulation process. The bitter tastewould reduce the abuse of oxycodone by oral or intranasal route. Theoxycodone formulation of Example 9 is listed in Table 9 below.

TABLE 9 Ingredients Amt/Unit (mg) Amount/Batch (gm) Oxycodone HCl 20.0209.6* Spray Dried Lactose 59.25 592.5 Povidone 5.0 50.0 Eudragit RS30D(solids) 10.0 100 Triacetin 2.0 20.0 Denatonium benzoate 0.07 0.68Stearyl Alcohol 25.0 250.0 Talc 2.5 25.0 Magnesium Stearate 1.25 12.5Opadry Pink Y-S-14518A 5.0 50.0 *adjusted for 99.6% assay and 4.2%residual moisture.

Process

-   1. Dispersion: Dissolve denatonium benzoate in water and the    solution is added to the Eudragit/Tracetin dispersion.-   2. Granulation: Spray the Eudragit/Triacetin dispersion onto the    Oxycodone HCl, Spray Dried Lactose and Povidone using a fluid bed    granulator.-   3. Milling: Discharge the granulation and pass through a mill.-   4. Waxing: Melt the stearyl alcohol and add to the milled    granulation using a mixer. Allow to cool.-   5. Milling: Pass the cooled granulation through a mill.-   6. Lubrication: Lubricate the granulation with talc and magnesium    stearate using a mixer.-   7. Compression: Compress the granulation into tablets using a tablet    press.

Example 10

In Example 10, a substantially non-releasable form of a bittering agent(denatonium benzoate) is prepared by coating denatonium benzoateparticles with a coating that renders the denatonium benzoatesubstantially non-releasable. The formula of Example 10 is listed inTable 10 below.

TABLE 10 Ingredients Amt/unit (mg) LOADING denatonium benzoate 0.07Sugar Spheres (30/35 mesh) 50.0 Opadry White Y-5-7068 2.5 Purified Water42.5* OVERCOATING Opadry White Y-5-7068 3.02 Purified Water 17.11*NON-RELEASE COATING (FOR RENDERING BITTERING AGENT SUBSTANTIALLYNON-RELEASABLE) Eudragit RS30D (dry wt.) 12.10 Triethyl Citrate 2.42Talc 4.84 Purified Water 49.21* OVERCOATING Opadry White Y-5-7068 4.12Purified Water 23.35* Total 79.07 *Remains in product as residualmoisture only.

Process:

-   -   1. Solution Preparation Dissolve the denatonium benzoate in        Purified Water. Once dissolved, add the Opadry White and        continue mixing until a homogeneous dispersion is yielded.    -   2. Loading Apply the above dispersion onto the Sugar Spheres        using a fluid bed coating machine.    -   3. Overcoating Prepare an overcoating solution by dispersing        Opadry White in Purified Water. Apply this dispersion over the        sugar spheres loaded with denatonium benzoate using a fluid bed        coating machine.    -   4. Retardant Coating Prepare the non-release coating solution by        mixing the Eudragit RS30D, Triethyl Citrate, Talc, and Purified        Water. Apply this dispersion over the loaded and overcoated        sugar spheres using a fluid bed coating machine.    -   5. Overcoating Prepare a second overcoating solution by        dispersing Opadry White in Purified Water. Apply this dispersion        over the non-release coated denatonium benzoate spheres using a        fluid bed coating machine    -   6. Curing Cure the spheres at 45° C. for approximately 48 hours.

Example 11

In Example 11, a substantially non-releasable form of a bittering agent(denatonium benzoate) is prepared as denatonium benzoate containinggranulates. The granulates are comprised of denatonium benzoatedispersed in a matrix that renders the denatonium benzoate substantiallynon-releasable. The formula of Example 11 is listed in Table 11 below.

TABLE 11 Ingredient Amt/unit (mg) Denatonium benzoate 0.07 DicalciumPhosphate 53.0 Poly (DI-Lactide-Co-Glycolide) 12.0 polymer (PLGA) MW~100,000 Ethyl Acetate Total 65.07 * Used as a vehicle for applicationof PLGA polymer.

Process:

-   -   1. Solution Preparation Dissolve PLGA in Ethyl Acetate by        mixing.    -   2. Granulation Place the denatonium benzoate, and Dicalcium        Phosphate in a fluid bed coating machine and granulate by        spraying the above solution.

Example 12

In Example 12 a substantially non-releasable form of a bittering agent(denatonium benzoate) is prepared as denatonium benzoate extrudedpellets. The formula of Table 12 is listed in Table 12 below.

TABLE 12 Ingredient Amt/unit (mg) Denatonium benzoate 0.07 Eudragit RSPO180.0 Stearyl Alcohol 55.0 Total 235.07

Process:

-   -   1. Milling Pass stearyl alcohol flakes through an impact mill.    -   2. Blending Mix Denatonium benzoate, Eudragit, and milled        Stearyl Alcohol in a twin shell blender.    -   3. Extrusion Continuously feed the blended material into a twin        screw extruder and collect the resultant strands on a conveyor.    -   4. Cooling Allow the strands to cool on the conveyor.    -   5. Pelletizing Cut the cooled strands into pellets using a        Pelletizer.    -   6. Screening Screen the pellets and collect desired sieve        portion.

Example 13 Controlled Release Oxycodone 20 mg

In Example 17, a sustained release 20 mg oxycodone formulation isprepared having the formulation listed in Table 13 below.

TABLE 13 Ingredients Amt/unit (mg) Oxycodone HCl 20.0 Spray DriedLactose 59.25 Povidone 5.0 Eudragit RS30D (solids) 10.0 Triacetin 2.0Stearyl Alcohol 25.0 Talc 2.5 Magnesium Stearate 1.25 Opadry PinkY-S-14518A 4.0 Total 129.0

Process:

-   1. Granulation: Spray the Eudragit/Triacetin dispersion onto the    Oxycodone HCl, Spray Dried Lactose and Povidone using a fluid bed    granulator.-   2. Milling: Discharge the granulation and pass through a mill.-   3. Waxing: Melt the stearyl alcohol and add to the milled    granulation using a mixer. Allow to cool.-   4. Milling: Pass the cooled granulation through a mill.-   5. Lubrication: Lubricate the granulation with talc and magnesium    stearate using a mixer.-   6. Compression: Compress the granulation into tablets using a tablet    press.-   7. Film coating: Apply an aqueous film coat to the tablets.

One or more aversive agents as described herein can be incorporated intothe oxycodone tablets by one skilled in the art. The one or moreaversive agents may be in releasable, non-releasable, or substantiallynon-releasable form or a combination thereof.

Example 14 Controlled Release Hydrocodone

A sustained release hydrocodone formulation is prepared having theformula in Table 14 below.

TABLE 14 Ingredient Amt/unit (mg) Amt/batch (g) Hydrocodone Bitartrate15.0 320.0 Eudragit RSPO 76.0 1520.0 Eudragit RLPO 4.0 80.0 StearylAlcohol 25.0 500.0 Total 120.0 2400.0

Process:

-   1. Blend milled Stearyl Alcohol, Eudragit RLPO, Hydrocodone    Bitartrate, and Eudragit RSPO using a Hobart Mixer.-   2. Extrude the granulation using a Powder Feeder, Melt Extruder    (equipped with the 6×1 mm die head), Conveyor, Lasermike, and    Pelletizer.    -   Powder feed rate—40 g/min; vacuum—980 mBar    -   Conveyor—such that diameter of extrudate is 1 mm    -   Pelletizer—such that pellets are cut to 1 mm in length-   3. Screen pellets using #16 mesh and #20 mesh screens. Collect    material that passes through the #16 mesh screen and is retained on    the #20 mesh screen.-   4. Fill size #2 clear gelatin capsules with the pellets. Range: NLT    (not less than) 114 mg and NMT (not more than) 126 mg.

One or more aversive agents as described herein can be incorporated intoa capsule with the hydrocodone pellets, into the hydrocodone pellets, oron the hydrocodone pellets by one skilled in the art. The one or moreaversive agents may be in releasable, non-releasable, or substantiallynon-releasable form or a combination thereof. Preferably, when pelletscomprising the aversive agent(s) are incorporated into the capsule theyare indistinguishable from the hydrocodone pellets.

Example 15 Oxycodone HCl beads for Capsule Lot #814-40

A sustained release oxycodone HCl bead formulation is prepared havingthe formula in Table 15 below.

TABLE 15 Ingredients Amt/unit* (mg) Step 1. Drug layering Oxycodone HCl10.5 Non-pareil beads 45.349 (30/35 mesh) Opadry Clear 2.5 Step 2.Sustained Eudragit RS30D (dry) 7.206 release coat Eudragit RL30D (dry)0.379 Triethyl citrate 1.517 Cabosil 0.379 Step 3. Seal coat OpadryClear 1.899 (Hydroxypropylmethyl cellulose) Cabosil 0.271 Total 70.0

Process:

-   1. Dissolve oxycodone HCl and Opadry (HPMC) in water. Spray the drug    solution onto non-pareil beads in a fluid bed coater with Wurster    insert.-   2. Disperse Eudragit RS, Eudragit RL, triethyl citrate, and Cabosil    in water. Spray the dispersion onto the beads in the fluid bed    coater.-   3. Dissolve Opadry in water. Spray the solution onto the beads in    the fluid bed coater.-   4. Cure the beads at 60° C. for 24 hours.

One or more aversive agents as described herein can be incorporated intoa capsule with the oxycodone beads, into the oxycodone beads, or on theoxycodone beads by one skilled in the art. The one or more aversiveagents may be in releasable, non-releasable, or substantiallynon-releasable form or a combination thereof. Preferably, when beadscomprising the aversive agent(s) are incorporated into the capsule theyare indistinguishable from the oxycodone beads.

Example 16 Controlled Release Hydromorphone

A sustained release hydromorphone HCl formulation is prepared having theformula in Table 16 below:

TABLE 16 Ingredients Amt/unit (mg) Hydromorphone HCI 12.0 Eudragit RSPO76.5 Ethocel 4.5 Stearic acid 27.0 Total 120.0

Process:

-   1. Blend milled Stearic acid, ethocel, Hydrocodone Bitartrate, and    Eudragit RSPO using a V-blender.-   2. Extrude the mixture using a Powder Feeder, Melt Extruder    (equipped with the 6×1 mm die head), Conveyor, Lasermike, and    Pelletizer.    -   Powder feed rate—4.2 kg/hr; vacuum—980 mBar    -   Conveyor—such that diameter of extrudate is 1 mm    -   Pelletizer—such that pellets are cut to 1 mm in length-   3. Screen pellets using #16 mesh and #20 mesh screens. Collect    material that passes through the #16 mesh screen and is retained on    the #20 mesh screen.-   4. Fill size #2 clear gelatin capsules with the pellets. Range: NLT    114 mg and NMT 126 mg.

One or more aversive agents as described herein can be incorporated intoa capsule with the hydromorphone pellets, into the hydromorphonepellets, or on the hydromorphone pellets by one skilled in the art. Theone or more aversive agents may be in releasable, non-releasable, orsubstantially non-releasable form or a combination thereof. Preferably,when pellets comprising the aversive agent(s) are incorporated into thecapsule they are indistinguishable from the hydromorphone pellets.

Example 17-20

Examples 9-12 can be repeated utilizing a sufficient amount of capsaicinin place of, or in

1-40. (canceled)
 41. A controlled release oral solid dosage formcomprising: (i) particles comprising an opioid analgesic and (ii)particles comprising polyethylene oxide, the dosage form providing atherapeutic effect for about 12 hours to about 24 hours when orallyadministered to a human patient, and when dissolved in from about 0.5 mlto about 10 ml of an aqueous liquid, forming a viscous gel, wherein theparticles comprising polyethylene oxide are free from the opioidanalgesic.
 42. The controlled release oral solid dosage form of claim41, wherein the viscous gel is unsuitable for injection.
 43. Thecontrolled release oral solid dosage form of claim 41, wherein theparticles comprising polyethylene oxide comprise a hydrophobic material.44. The controlled release oral solid dosage form of claim 43, whereinthe hydrophobic material is an ammonio methacrylate copolymer.
 45. Thecontrolled release oral solid dosage form of claim 41, wherein theviscous gel cannot be injected through an insulin syringe.
 46. Thecontrolled release oral solid dosage form of claim 41, wherein theparticles comprising polyethylene oxide comprise polyvinylpyrrolidone.47. The controlled release oral solid dosage form of claim 44, whereinthe particles comprising the opioid analgesic and the particlescomprising polyethylene oxide are contained in a pharmaceuticallyacceptable capsule.
 48. The controlled release oral solid dosage form ofclaim 47, wherein the particles comprising the opioid analgesic and theparticles comprising polyethylene oxide are indistinguishable inappearance.
 49. The controlled release oral solid dosage form of claim41, wherein the viscous gel cannot be drawn into an insulin syringe. 50.The controlled release oral solid dosage form of claim 41, wherein theparticles comprising the opioid analgesic have a diameter from about 0.5mm to about 2.5 mm.
 51. The controlled release oral solid dosage form ofclaim 41, wherein the polyethylene oxide is in an effective amount toimpart a viscosity of at least about 10 cP to the dosage form when thedosage form is dissolved in from about 0.5 ml to about 10 ml of anaqueous liquid.
 52. The controlled release oral solid dosage form ofclaim 41, wherein the polyethylene oxide is in an effective amount toimpart a viscosity of at least about 60 cP to the dosage form when thedosage form is dissolved in from about 0.5 ml to about 10 ml of anaqueous liquid.
 53. The controlled release oral solid dosage form ofclaim 41, wherein the polyethylene oxide is in an effective amount toimpart a viscosity of from 120 cP to 5000 cP to the dosage form when thedosage form is dissolved in from about 0.5 to about 10 ml of an aqueousliquid.
 54. The controlled release oral solid dosage form of claim 41,wherein the polyethylene oxide is in an effective amount to impart aviscosity of from 375 cP to 5000 cP to the dosage form when the dosageform is dissolved in from about 0.5 ml to about 10 ml of an aqueousliquid.
 55. The controlled release oral solid dosage form of claim 41,wherein the polyethylene oxide is in an effective amount to impart aviscosity of from 2,000 cP to 5000 cP to the dosage form when the dosageform is dissolved in from about 0.5 ml to about 10 ml of an aqueousliquid.
 56. The controlled release oral solid dosage form of claim 41,wherein the polyethylene oxide is in an effective amount to impart aviscosity of from 120 cP to 5,000 cP when the dosage form is dissolvedin from about 0.5 ml to about 10 ml of an aqueous liquid.
 57. Acontrolled release oral solid dosage form comprising a capsulecontaining: (i) particles comprising an opioid analgesic and (ii)particles comprising polyethylene oxide, the dosage form providing atherapeutic effect for about 12 hours when orally administered to ahuman patient, and having a viscosity unsuitable for injection whendissolved in from about 0.5 ml to about 10 ml of water, wherein theparticles comprising polyethylene oxide are free from the opioidanalgesic.
 58. The controlled release oral solid dosage form of claim57, wherein the polyethylene oxide is in an effective amount to impart aviscosity of from 375 cP to 5000 cP when the dosage form is dissolved infrom about 0.5 ml to about 10 ml of water.
 59. The controlled releaseoral solid dosage form of claim 57, wherein the polyethylene oxide is inan effective amount to impart a viscosity of from 2000 cP to 5000 cPwhen the dosage form is dissolved.
 60. The controlled release oral soliddosage form of claim 57, wherein the polyethylene oxide is in aneffective amount to impart a viscosity of from 120 cP to 5,000 cP whenthe dosage form is dissolved in from about 0.5 ml to about 10 ml ofwater.
 61. A controlled release oral solid dosage form comprising acapsule containing: (i) particles comprising an opioid analgesic and(ii) particles comprising polyethylene oxide, the dosage form providinga therapeutic effect for about 12 hours to about 24 hours when orallyadministered to a human patient, and when dissolved in from about 0.5 mlto about 10 ml of water, forming a viscous gel, wherein the particlescomprising polyethylene oxide are free from the opioid analgesic. 62.The controlled release oral solid dosage form of claim 61, wherein theparticles comprising the polyethylene oxide and the particles comprisingthe opioid analgesic are indistinguishable in appearance.
 63. Thecontrolled release oral solid dosage form of claim 66, wherein thepolyethylene oxide is in an effective amount to impart a viscosity offrom 10 cP to 60 cP when the dosage form is dissolved in from about 0.5ml to about 10 ml of an aqueous liquid.
 64. The controlled release oralsolid dosage form of claim 66, wherein the polyethylene oxide is in aneffective amount to impart a viscosity of from 120 cP to 5,000 cP whenthe dosage form is dissolved in from about 0.5 ml to about 10 ml of anaqueous liquid.